Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment

ABSTRACT

The present invention is directed to novel taxanes useful as chemotherapeutic agents or their precursors. Processes for preparing the novel taxanes include coupling reactions, in the presence of a base, of baccatin of formula (III) or (IV) ##STR1## with β-lactams of formula (V). ##STR2## The invention also provides pharmaceutical compositions including the novel taxanes and method for treatment of certain cancers with these new compounds.

This work was in part supported by a grant form the National Instituteof Health (GM42798).

BACKGROUND OF THE INVENTION

The invention relates to new taxanes possessing strong antitumoractivities, precursors of these compounds, compositions including thesecompounds, and processes for synthesizing these compounds and methodsfor treating tumors by using these new compounds.

Taxol is currently considered the most exciting "lead" compound incancer chemotherapy. Taxol is a complex diterpene isolated from the barkof Taxus Brevifolia (Pacific Yew). Taxol possesses high cytotoxicity andstrong antitumor activity against different cancers which have not beeneffectively treated by existing antitumor drugs. For example, taxol hasbeen approved by FDA in late 1992 for the treatment of advanced ovariancancer, and is currently in phase II clinical trials for breast and lungcancers.

Although Taxol is an important "lead" compound in cancer chemotherapy,Taxol has limited solubility in aqueous media, resulting in seriouslimitations to its use. It is also common that better drugs can bederived from naturally occurring "lead" compounds. In fact, Frenchresearchers have discovered a new anticancer agent by modifying the C-13side chain of Taxol. This unnatural compound, named "Taxotere" hast-butoxycarbonyl instead of benzoyl on the amino group of (2R,3S)-phenylisoserine moiety at the C-13 position and a hydroxyl groupinstead of acetoxy group at C-10. Taxotere has antitumor activitysuperior to Taxol with better bioavailability. Taxotere is currently inphase II clinical trials in the United States, Europe, and Japan.

Taxol and Taxotere have chemical structures as follows: ##STR3##

A recent report on clinical trials of Taxol and Taxotere has disclosedthat Taxol has side effects such as nerve damage, muscle pain ordisturbances in heart rhythm. Taxotere also has side effects. Forexample, Taxotere provokes mouth sores and a plunge in white blood cellcount. There are other minor side effects for these two drugs.

Taxol's poor water solubility causes practical problems in itspharmaceutical applications. For example, pharmaceutical formulationscontaining Taxol may require special carriers. Maximum dosages in Taxoldrugs are also limited by the solubility of Taxol.

Taxotere, on the other hand, has a somewhat improved water solubilityand thus better pharmacological properties than Taxol, but thisantitumor agent also has a solubility problem.

It has been found that 14-Hydroxy-10-deacetylbaccatin III (14-OH-DAB),##STR4## has much higher water solubility than the usual10-deacetylbaccatin III. 10-deacetylbaccatin III is currently used forproduction of Taxol and Taxotere. This higher solubility of 14-OH-DAB isdue to an extra hydroxyl group at the C-14 position. Therefore, newantitumor taxanes derived from 14-OH-DAB are expected to havesubstantially improved water solubility and pharmacological propertiesas therapeutic agents. The improved pharmacological properties arebelieved to be related to modifications in toxicity and activity spectraagainst different types of cancer.

Accordingly, it is an object of the invention to develop new anti-tumoragents of the Taxol or Taxotere class which have distinct structuraldifferences which enhance solubility.

It is a further object of the present invention to provide a series ofnew taxanes derived from 14-OH-DAB which possess strong antitumoractivities with better therapeutic profile. It is yet another object ofthe present invention to synthesize the new taxanes in high yield with aminimum number of syntheses steps.

SUMMARY OF THE INVENTION

Compounds of the formula (I) ##STR5## or the formula (II) ##STR6## areuseful as antitumor agents or their precursors.

In these compounds R¹ represents an unsubstituted or substitutedstraight chain or branched alkyl, alkenyl or alkynyl, an unsubstitutedor substituted aryl or heteroaryl radical, an unsubstituted orsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl orheterocycloalkenyl radical;

R² is an unsubstituted or substituted straight chain or branched alkyl,alkenyl or alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl or heteroaryl;

or R² can also be an RO--, RS-- or RR'N-- in which R represents anunsubstituted or substituted straight chain or branched alkyl, alkenylor alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl or heteroaryl; R' is a hydrogen or R is asdefined above; R and R' can be connected to form a cyclic structure;

R³ represents a hydrogen or an acyl or an alkyl or an alkenyl or analkynyl or an unsubstituted or substituted cycloalkyl, heterocycloalkyl,cycloalkenyl or heterocycloalkenyl radical, or an unsubstituted orsubstituted aryl or heteroaryl radical or a hydroxyl protecting group;

R⁴ represents a hydrogen or an acyl radical or an alkyl, alkenyl oralkynyl radical, an unsubstituted or substituted cycloalkyl,heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, anunsubstituted or substituted aryl or heteroaryl radical, or a hydroxylprotecting group;

R⁵ represents a hydrogen or an acyl radical or an alkyl, alkenyl oralkynyl radical, an unsubstituted or substituted cycloalkyl,heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, anunsubstituted or substituted aryl or heteroaryl radical, or a hydroxylprotecting group;

R⁶ represents a hydrogen or an acyl radical or an alkyl, alkenyl oralkynyl radical, an unsubstituted or substituted cycloalkyl,heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, anunsubstituted or substituted aryl or heteroaryl radical, or a hydroxylprotecting group;

R⁵ and R⁶ can be connected to form a cyclic structure;

R⁷ represents an acyl group;

R⁸ represents a hydrogen or a hydroxyl protecting group.

The new taxanes (I) and (II) are synthesized by processes which comprisecoupling reactions, in the presence of a base, of baccatin of theformula (III) ##STR7## in which G₁, G₂, G₃ and G₄ represent a hydroxylprotecting group or an acyl or an alkyl or an alkenyl or an alkynyl oran unsubstituted or substituted cycloalkyl, heterocycloalkyl,cycloalkenyl or heterocycloalkenyl radical, or an unsubstituted orsubstituted aryl or heteroaryl radical; G₃ and G₄ can be connected toform a cyclic structure; R⁶ has been defined above;

or of the formula (IV) ##STR8## in which G₁, G₂, G₄, and R⁶ have beendefined above; with β-lactams of the formula (V) ##STR9## in which G isa hydroxyl protecting group such as ethoxyethyl (EE), triethylsilyl(TES) and dimethyl(tert-butyl)silyl (TBDMS), and R¹ and R² have beendefined above.

The new taxanes of the present invention have shown strong antitumoractivities against human breast, non-small cell lung, ovarian, and coloncancer cells. It is therefore very important to develop new anti-cancerdrugs which have fewer undesirable side effects, better pharmacologicalproperties, and/or activity spectra against various tumor typesdifferent from both Taxol and Taxotere.

For a better understanding of the present invention, together with otherand further objects, reference is made to the following description andits scope will be pointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The new taxanes of formulae (I) or (II), as shown above, are useful asantitumor agents or their precursors. The taxanes of the presentinvention possess strong antitumor activities against human breast,non-small cell lung, ovarian, and colon cancer cells.

The new taxanes of the formula (I) are synthesized by modifying thebaccatin of formula (III) in which ##STR10## G₁, G₂, G₃, G₄, and R⁷ havebeen defined above.

The new taxanes of formula (II) are synthesized by modifying thebaccatin of formula (IV) ##STR11## in which G₁, G₂, G₄, and R⁷ have beendefined above.

Precursors of (III) and (IV) are readily available. Both baccatins (III)and (IV) may be prepared by chemically modifying14β-hydroxy-10-deacetylbaccatin (14-OH-DAB), a naturally occurringcompound found in Himalayan Yew. Methods of isolations of 14-OH-DAB havebeen described by Appendino et al. in "14β-Hydroxy-10-deacetylbaccatinIII, a New Taxane from Himalayan Yew." J. Chem. Soc. Perkin Trans I,2525-2529 (1992), the contents of which are incorporated herein byreference.

Baccatins (III) and (IV) are coupled with β-lactams of formula (V)##STR12## in which G, R¹ and R² have been defined above, to yield thenew taxanes (I) and (II), respectively.

β-lactams (V) are readily prepared from β-lactams (VI) which are easilyobtained through a chiral enolateimine cyclocondensation methoddeveloped in one of the inventors' laboratory as shown in Scheme 1. Thecyclocondensation is described in Ojima et al., Tetrahedron, 1992, 48,6985; Ojima, I. et al., J. Org. Chem., 56, 1681, (1991), and in U.S.patent application No. 07/842,444 filed on Feb. 27, 1992 the contents ofwhich are incorporated herein by reference in their entirety. In thispreparation, β-lactams (VI) are obtained in high yields with extremelyhigh enantiomeric purities. Scheme 1 illustrates the synthesis of achiral β-lactam. In Scheme 1, R* is a chiral auxiliary moiety which maybe (-)-trans-2-phenyl-1-cyclohexyl,(-)-10-dicyclohexylsulfamoyl-D-isobornyl or (-)-menthyl; TMS is atrimethylsilyl radical; the base is lithium diisopropylamide or lithiumhexamethyldisilazide; and G and R¹ have been defined above. The removalof the 4-methoxy phenyl group from the N-position (VI') to obtainβ-lactams (VI) is accomplished by treatment with cerium ammonium nitrate(CAN). ##STR13##

Referring now to Scheme 2, β-lactams (VIa) where G is triisopropylsilyl(TIPS) may be converted to the 3-hydroxy-β-lactams (VII), followed byprotection with groups such as ethoxyethyl (EE) or triethylsilyl (TES)to give β-lactams (VI). The protecting groups can be attached to thehydroxyl group of β-lactams (VI) by methods which are generally known tothose skilled in the art. β-Lactams (VI) where G is(tert-butyl)dimethylsilyl (TBDMS), may be directly obtained from thechiral enolate-imine cyclocondensation described above. β-Lactams (VI)may be reacted with acyl chlorides, chloroformates, and carbamoylchlorides in the presence of a base to yield β-lactams (V). Theβ-lactams (V) may be coupled with baccatin (III) or (IV).

Scheme 3 and 4 illustrate the coupling of β-lactams (V) baccatins (III)or (IV) in the presence of a base, followed by deprotection to yield thenew taxanes (I) or (II), respectively in high yields. ##STR14##

The taxanes thus obtained are represented by formulae I and II shownabove. R¹ through R⁸ are as generally defined above R¹, R² and R areeach independently a straight chain or branched alkyl radical containing1 to 10 carbon atoms, a straight chain or branched alkenyl radicalcontaining 2 to 10 carbon atoms, or a straight chain or branched alkynylradical containing 2 to 10 carbon atoms, a cycloalkyl radical containing3 to 10 carbon atoms, a heterocycloalkyl radical containing 3 to 10carbon atoms, a cycloalkenyl radical containing 3 to 10 carbon atoms, aheterocycloalkenyl radical containing 3 to 10 carbon atoms, apolycycloalkyl radical containing 6 to 20 carbon atoms, an aryl radicalcontaining 6 to 20 carbons, a heteroaryl radical containing 3 to 15carbon atoms; or R² can also be RO--, RS-- or RR'N-- radical in which Ris as defined above;

R' is a hydrogen or can also be R as defined above; R and R' can beconnected to form a cyclic structure which has 2 to 10 carbon atoms;

R³, R⁴, R⁵ or R⁶ are each independently hydrogen or an acyl radicalhaving 1 to 20 carbons or R as defined above or a hydroxyl protectinggroup;

R⁷ is an acyl group having 1 to 20 carbons;

R⁸ is a hydrogen or a hydroxyl protecting group.

Heteroaromatic groups may also include atoms of oxygen, nitrogen andsulfur. In addition, with respect to formula (I) and (II) above, R³ canalso be a hydrogen or G₁ ; R⁴ can also be a hydrogen or G₂ ; R⁵ can alsobe a hydrogen or G₃ ; R⁶ can also be a hydrogen or G₄ ; and R⁸ can alsobe a hydrogen or G, in which G, G₁, G₂, G₃ and G₄ have been previouslydefined.

Each radical in R¹, R² and R as defined above can be optionallysubstituted with one or more halogens, hydroxyl, amino, mercapto, cyano,carboxyl group, alkoxy, alkylamino, dialkylamino, alkylthio,alkoxycarboxyl group in which said alkyl portion has 1 to 15 carbonatoms aryloxy, arylthio, aryloxycarbonyl, in which said aryl portion has6 to 20 carbon atoms, or heteroarylthio, heteroaryloxy carbonyl in whichsaid heteroaryl portion has 3 to 15 carbon atoms.

In one embodiment, R¹ can also be an alkyl radical selected from thegroup consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl,isoheptyl, octyl, isooctyl, cyclohexylmethyl, cyclohexylethyl, benzyl,phenylethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and adamantyl, or an alkenyl radical selectedfrom the group consisting of vinyl, allyl, 2-phenylethenyl,2-furylethenyl, 2-pyrrolyl-ethenyl, 2-pyridylethenyl, 2-thienylethyl, oran an unsubstituted or substituted alkynyl radical selected from thegroup consisting of ethynyl and propargyl or an aryl radical selectedfrom the group consisting of phenyl, tolyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl,4-chlorophenyl, and naphthyl; or a heteroaryl radical selected from thegroup consisting of furyl, pyrrolyl, and pyridyl, or a cycloalkenylradical selected from the group consisting of cyclopentenyl,cyclohexenyl and cycloheptenyl or a heterocycloalkyl selected from thegroup consisting of oxiranyl, pyrrolidinyl, piperidinyl,tetrahydrofuryl, and tetrahydropyranyl, or a heterocycloalkenyl radicalselected from the group consisting of dihydrofuryl, dihydropyrrolyl,dihydropiranyl, and dihydropyridyl;

R² is an unsubstituted or substituted alkyl, alkenyl, alkynyl, aryl orheteroaryl radical selected from the group consisting of phenyl, tolyl,4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, biphenyl, 1-naphthyl,2-naphthyl, isopropyl, isobutyl, neopentyl, hexyl, heptyl, cyclohexyl,cyclohexylmethyl, benzyl, phenylethyl, phenylethenyl, crotyl, allyl,vinyl, propargyl, pyridinyl, furyl, thienyl, pyrrolidinyl, andpiperidinyl; or R² is RO--, RS--, or RR'N-- wherein R is anunsubstituted or substituted alkyl radical selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl,isoheptyl, octyl, isooctyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl, or an alkenylradical selected from the group consisting of vinyl and allyl, or anaryl radical selected from phenyl and naphthyl, or a heteroaryl radicalselected from the group consisting of furyl, pyrrolyl, and pyridyl, or acycloalkenyl radical selected from the group consisting ofcyclopentenyl, cyclohexenyl and cycloheptenyl, or a heterocycloalkylradical selected from the group consisting of an oxiranyl,tetrahydrofuryl, pyrrolidinyl, piperidinyl, and tetrahydropiranyl, or aheterocycloalkenyl radical selected from the group consisting ofdihydrofuryl, dihydropyrrolyl, dihydropiranyl, dihydropyridyl; R' is ahydrogen or R is as defined above; cyclic RR'N-- is a radical includingan aziridino, azetidino, pyrrolidino, piperidino or morpholino group;

wherein said hydroxyl protecting group is selected from the groupconsisting of methoxymethyl, methoxyethyl, 1-ethoxyethyl,benzyloxymethyl, (β-trimethylsilylethoxyl)methyl, tetrahydropyranyl,2,2,2-trichloroethoxylcarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl,9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxymethyl, trimethylsilyl,triethylsilyl, tripropylsilyl, dimethylethylsilyl,dimethyl(t-butyl)silyl, diethylmethylsilyl, dimethylphenylsilyl anddiphenylmethylsilyl;

said acyl is selected from the group consisting of acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl and trifluoroacetyl, propanoyl,butanoyl, pentanoyl, hexanoyl, heptanoyl, cyclohexanecarbonyl, octanoyl,nonanoyl, decanoyl, undecanoyl, dodecanoyl, benzoyl, phenylacetyl,nanphthalenecarbonyl, indoleacetyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, and butoxycarbonyl; and

R⁵ and R⁶ form a cyclic structure with two oxygen atoms of the skeletonof said taxane, wherein said cyclic structure is selected from the groupconsisting of carbonate, methylacetal, ethylacetal, propylacetal,butylacetal, phenylacetal, dimethylketal, diethylketal, dipropylketal,and dibutylketal.

In another embodiment R¹ may be phenyl, tolyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-fluorophenyl, 4-trifluoromethyl-phenyl,4-hydroxyphenyl, 1-naphthyl, 2naphthyl, pyridyl, furyl, thienyl,pyrrolyl, N-methylpyrrolyl, 2-phenylethenyl, 2-furylethenyl,2-pyridylethenyl, 2-thienylethenyl, 2-phenylethyl, 2-cyclohexylethyl,cyclohexylmethyl, isobutyl or cyclohexyl;

R² is selected from the group consisting of phenyl, tolyl,4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, biphenyl, 1-naphthyl,2-naphthyl, isopropyl, isobutyl, neopentyl, hexyl, heptyl, cyclohexyl,cyclohexylmethyl, benzyl, phenylethyl, and phenylethenyl;

or R² is RO-- wherein R is selected from the group consisting of amethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, phenyl, benzyl and9-fluorenylmethyl;

or R² is RR'N-- selected from the group consisting of a methylamino,ethylamino, propylamino, isopropylamino, butylamino, isobutylamino,tert-butylamino, neopentylamino, cyclohexylamino, phenylamino orbenzylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino,dipentylamino, dihexylamino, dicyclohexylamino, methyl(tert-butyl)amino,cyclohexyl(methyl)amino, methyl(phenyl)amino, pyrrolidiono, piperidino,or morpholino group;

R³ and R⁴ are selected from the group consisting of a hydrogen, acetyl,chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl,benzoyl, phenylacetyl, acryloyl, and crotyl, cinnamoyl, allyl, benzyl,methoxymethyl, methoxyethyl, 1-ethoxyethyl, tetrahydropyranyl,2,2,2-trichloroethoxylcarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl,9-fluroenylmethoxycarbonyl, trimethylsilyl, triethylsilyl,(tert-butyl)dimethylsilyl;

R⁵ is selected from the group consisting of a hydrogen, acetyl,chloroacetyl, allyl, benzyl, acryloyl, crotyl, and cinnamoyl and R⁶ is ahydrogen; wherein R⁵ and R⁶ are connected to form a cyclic structureselected from the group consisting of carbonyl, propylidene, butylidene,pentylidene, phenylmethylidene, dimethylmethylidene, diethylmethylidene,dipropylmethylidene, dibutylmethylidene, methoxymethylidene,ethoxymethylidene, methylene, ethylene, and propylene;

R⁷ is selected from the group consisting of benzoyl andcyclohexanecarbonyl;

R⁸ is selected from the group consisting of a hydrogen, 1-ethoxyethyl,2,2,2-trichloroethoxylcarbonyl, trimethylsilyl, triethylsilyl, andtert-butyldimethylsilyl.

Representative hydroxyl protecting groups include methoxylmethyl (MOM),methoxyethyl (MEM), 1-ethoxyethyl (EE), benzyloxymethyl,(β-trimethylsilylethoxyl)methyl, tetrahydropyranyl,2,2,2-trichloroethoxylcarbonyl (Troc), benzyloxycarbonyl (CBZ),tert-butoxycarbonyl (t-BOC), 9-fluorenylmethoxycarbonyl (Fmoc),2,2,2-trichloroethoxymethyl, trimethylsilyl, triethylsilyl,tripropylsilyl, dimethylethylsilyl, dimethyl(t-butyl)silyl,diethylmethylsilyl, dimethylphenylsilyl and diphenylmethylsilyl, acetyl,chloroacetyl, dichloroacetyl, trichloroacetyl or trifluoroacetyl.

The coupling reaction of baccatin (III) or (IV) and β-lactam (V), asshown in Schemes 3 and 4, occurs at an alkali metal alkoxide which islocated at the C-13 hydroxyl group of baccatin (III) or at the C-14hydroxyl group of baccatin (IV). The alkoxide can be readily generatedby reacting the baccatin with an alkali metal base.

Representative alkyl metal bases include sodium hexamethyldisilazide,potassium hexamethyldisilazide, lithium hexamethyldisilazide, sodiumdiisopropylamide, potassium diisopropylamide, lithium diisopropylamide,sodium hydride, in a dry nonprotic organic solvent. Tetrahydrofuran(THF), dioxane, ether, dimethoxyethane (DME), diglyme, dimethylformamide(DMF), or mixtures of these solvents with hexane, toluene, and xyleneare useful nonprotic organic solvents. The coupling reaction ispreferrably carried out in a temperature range from about -100° C. toabout 50° C., and more preferably from about -50° C. to about 25° C.

The coupling reaction is also preferably carried out under an inert gasatmosphere such as nitrogen and argon. The amount of base used for thereaction is preferably approximately equivalent to the amount ofbaccatin when soluble bases such as sodium hexamethyldisilazide,potassium hexamethyldisilazide, lithium hexamethyldisilazide, sodiumdiisopropylamide, potassium diisopropylamide, lithium diisopropylamideare being used. The use of a slight excess of base does not adverselyaffect the reaction. When heterogeneous bases such as sodium hydride andpotassium hydride are used, 5-10 equivalents of the base to the amountof baccatin are preferably employed.

The coupling reaction at the metal alkoxide of baccatin is typicallycarried out by adding a solution of β-lactam in a dry non-protic organicsolvent, as described above, in a preferred temperature range from about-100° C. to 50° C., and more preferably from about -50° C. to 25° C. Themixture of reactants is stirred for 15 minutes to 24 hours and theprogress and completion of the reaction may be monitored by knownmethods such as thin layer chromatography (TLC). When the limitingreactant is completely consumed, the reaction is quenched by addition ofa cold brine solution. The crude reaction mixture is worked up usingstandard isolation procedures, generally known to those skilled in theart, to yield the corresponding taxane. The ratio of β-lactam tobaccatin is in a range from 2:1 to 1:2. More preferably a ratio ofapproximately 1:1 has been formed to be more economic and efficient, butthis ratio is not critical for the reaction. Work-up means any routineisolation procedure used to obtain the product from the reactionmixture.

The hydroxyl protecting groups can then be removed by using standardprocedures which are generally known to those skilled in the art to givedesired taxane derivatives. For example, 1-ethoxyethyl and triethylsilylgroups can be removed by adding 0.5N HCl at room temperature for 36hours. A Troc group can be removed by adding with zinc and acetic acidin methanol at 60° C. for one hour without disturbing other functionalgroups or the skeleton of taxane. Another method of deprotection istreating triisopropylsilyl (TIPS) or (tert-butyl)dimethylsilyl (TBDMS)groups with fluoride ion.

The compounds of the invention can be formulated in pharmaceuticalpreparations or formulated in the form of pharmaceutically acceptablesalts thereof, particularly as nontoxic pharmaceutically acceptable acidaddition salts or acceptable basic salts. These salts can be preparedfrom the compounds of the invention according to conventional chemicalmethods.

Normally, the salts are prepared by reacting the free base or acid withstoichiometric amounts or with an excess thereof of the desired saltforming inorganic or organic acid in a suitable solvent or variouscombination of solvents. As an example, the free base can be dissolvedin an aqueous solution of the appropriate acid and the salt recovered bystandard techniques, for example, by evaporation of the solution.Alternatively, the free base can be dissolved in an organic solvent suchas a lower alkanol, an ether, an alkyl ester, or mixtures thereof, forexample, methanol, ethanol, ether, ethyl acetate, an ethyl acetate-ethersolution, and the like, whereafter it is treated with the appropriateacid to form the corresponding salt. The salt is recovered by standardrecovery techniques, for example, by filtration of the desired salt onspontaneous separation from the solution or it can be precipitated bythe addition of a solvent in which the salt is insoluble and recoveredtherefrom.

Due to their antineoplastic activity, the taxane compounds of theinvention can be utilized in the treatment of cancers. The new compoundsare administrable in the form of tablets, pills, powder mixtures,capsules, injectables, solutions, suppositories, emulsions, dispersions,food premix, and in other suitable forms. The pharmaceutical preparationwhich contains the compound is conveniently admixed with a nontoxicpharmaceutical organic carrier, usually about 0.01 mg up to 2500 mg. orhigher per dosage unit, preferably 50-500 mg. Typical ofpharmaceutically acceptable carriers are, for example, manitol, urea,dextrans, lactose, potato and maize starches, magnesium stearate, talc,vegetable oils, polyalkylene glycols, ethyl cellulose,poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropylmyristate, benzyl benzoate, sodium carbonate, gelatin, potassiumcarbonate, silicic acid, and other conventionally employed acceptablecarriers. The pharmaceutical preparation may also contain nontoxicauxiliary substances such as emulsifying, preserving, wetting agents,and the like as for example, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctylsodium sulfosuccinate, and the like.

The compounds of the invention can also be freeze dried and, if desired,combined with other pharmaceutically acceptable excipients to prepareformulations suitable for parenteral, injectable administration. Forsuch administration, the formulation can be reconstituted in water(normal, saline), or a mixture of water and an organic solvent, such aspropylene glycol, ethanol, and the like.

The dose administered, whether a single dose, multiple dose, or a dailydose, will, of course, vary with the particular compound of theinvention employed because of the varying potency of the compound, thechosen route of administration, the size of the recipient and the natureof the patient's condition. The dosage administered is not subject todefinite bounds, but it will usually be an effective amount, or theequivalent on a molar basis of the physiologically active free formproduced from a dosage formulation upon the metabolic release of theactive drug to achieve its desired pharmacological and physiologicaleffects.

The following non-limiting examples are illustrative of the presentinvention. The full scope of the invention will be pointed out in theclaims which follow the specification.

EXAMPLES

β-lactams (VI) were obtained as shown in Scheme 1 through a chiralenolate-imine cyclocondensation method in which silyloxyacetates (A)were reacted with imines or aldimines (B) and (B') in the presence of abase such as lithium diisopropylamide or lithium hexamethyldisilazide.Procedures for obtaining the starting compounds (A) and (B) or (B') aredescribed in Examples 1-12. The materials used in Examples 1-12 in thepreparation of materials (A), (B) and (B') are readily commerciallyavailable.

Example 1 Preparation of (-)-(1R,2S)-2-phenyl-1-cyclohexyltriisopropylsilyloxyacetate (A)

A solution of (-)-(1R, 2S)-2-phenyl-1-cyclohexyl hydroxyacetate (851 mg,3.63 mmol) was prepared through esterification of benzyloxyacetylchloride with (-)-(1R,2S)-2-phenyl-1-cyclohexanol followed byhydrogenolysis. Then, triisopropylsilyl chloride (840 mg, 4.36 mmol) andimidazole (618 mg, 9.08 mmol) in dimethylformamide (DMF) (1.7 mL) werestirred at room temperature for 12-20 hours. The mixture was poured intopentane (25 mL), and washed with water and brine. The combined organiclayers were dried over anhydrous MgSO₄ and concentrated in vacuo. Thecrude product was subjected to a purification on a short silica gelcolumn using hexane/chloroform (3/1) as the eluant to give pure (-)-(1R,2S)-2-phenyl-1-cyclohexyl triisopropylsilyloxyacetate (1.35 g, 95%yield) as a colorless oil.

Identification data for the above triisopropylsilyloxy-acetate are shownbelow:

[α]_(D) ²⁰ -17.1° (c 3.15, CHCl₃); IR (neat) 1759, 1730 ('CO) cm⁻¹ ; ¹ HNMR (CDCl₃) δ0.93-0.99 (m, 21H), 1.30-1.62 (m, 4H), 1.72-2.0 (m, 3H),2.10-2.19 (m, 1H), 2.66 (dt, J =11.5, 4.0 Hz, 1H), 3.90 (d, J=16.6 Hz,1H), 4.07 (d, J=16.6 Hz, 1H), 5.07 (dt, J=10.6, 4.0 Hz, 1H), 7.16-7.30(m, 5H). Anal. Calcd for C₂₃ H₃₈ O₃ Si: C, 70.72; H, 9.81. Found: C,70.79; H, 9.85

Examples 2-4 Preparations of N-trimethylsilylimines (B)

N-Trimethylsilylaldimines used in the cyclo-condensation method can bereadily obtained by the reaction of lithium hexamethyldisilazide withaldehydes. A typical procedure for the preparation ofN-trimethylsilylbenzaldimine is described below.

In 75 mL of anhydrous THF were added 17.29 mL (75 mmol) ofhexamethyldisilazane and 30 mL (75 mmol) of N-butyllithium (2.5M inhexane) at 0° C. under nitrogen. After stirring for one hour, 7.65 mL(75 mmol) of benzaldehyde was added at room temperature, and the mixturewas refluxed for 3 hours. Then, 9.52 mL (75 mmol) of freshly distilledtrimethylsilyl chloride was added with a syringe. The mixture wasrefluxed for 2 hours. A white precipitate formed during this process.The reaction mixture was then cooled to room temperature and the liquidlayer was transferred with a syringe to a distillation flask undernitrogen. The solvent was evaporated in vacuo, and the oily residue wasdistilled under reduced pressure (68° C./1 mm Hg) to give pureN-trimethylsilylbenzaldimine as a pale yellow oil (10.6 g, 80%) havingthe identification data shown below:

¹ H NMR (CDCl₃) δ0.18 (s, 9 H), 7.33-7.36 (m, 3H), 7.72-7.75 (m, 2H),8.89 (s, 1H); ¹³ C NMR (CDCl₃) δ-1.25, 128.34, 128.39, 131.96, 138.70,168.32

N-trimethylsilyl(4-methoxy)benzaldimine andN-trimethylsilyl-(3,4-dimethoxy)benzaldimine were prepared in the samemanner, from 4-methoxybenzaldehyde and 3,4-dimethoxy-benzaldehyde,respectively, in 78-82% yields. Identification data for the imines isset forth next to each one of these compounds.

Example 3 N-Trimethylsilyl(4-methoxy)benzaldimine

Pale yellow oil; bp 105° C./0.4 mmHg; ¹ H NMR (CDCl₃) δ0.00 (s, 9H),3.60 (s, 3H), 6.69 (d, J=8.7 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 8.66 (s,1H).

Example 4 N-Trimethylsilyl-(3,4-dimethoxy)benzaldimine

Colorless oil; bp 140° C./0.2 mmHg; ¹ H NMR δ0.00 (s, 9H), 3.67 (s, 3H),3.71 (s, 3H), 6.65 (d, J=8.2 Hz, 1H), 7.01 (dd, J=8.2, 1.8 Hz, 1H), 7.22(d, J=1.8 Hz, 1H), 8.63 (s, 1H).

Examples 5-12 Preparations of N-(4-Methoxyphenyl)aldimines (B')

A typical procedure is described for the preparation ofN-(4-methoxyphenyl)(4-fluoro)benzaldimine. To a solution of 4.81 g (39mmol) of p-anisidine in 60 mL of dichloromethane was added 4.85 g (39mmol) of 4-fluorobenzaldehyde. The mixture was stirred over anhydrousmagnesium sulfate at room temperature for 15 hours. The dehydrationagent was filtered off and the filtrate was concentrated in vacuo togive a crude imine. The crude imine was recrystallized fromhexane/dichloro/methane to yield 7.69 g (86%) of pureN-(4-methoxyphenyl) (4-fluoro)benzaldimine as white needles.

Identification data for this imine are shown below:

Mp 99° C.; ¹ H NMR (CDCl₃) δ3.82 (s, 3H), 6.92 (d, J=8.7 Hz, 2H), 7.13(t, J=8.6 Hz, 2H), 7.21 (d, J=8.7 Hz, 2H), 7.88 (dd, J=8.6, 5.7 Hz, 2H),8.39 (s,1H).

Other N-(4-methoxylphenyl)aldimines were prepared in high yields in thesame manner. Identification data for these imines are shown next to eachone of these compounds.

Example 6 N-(4-Methoxyphenyl)benzaldimine

White solid; mp 71°-72° C.; ¹ H NMR (CDCl₃) δ3.93 (s, 3H), 6.93 (d,J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.46 (m, 3H), 7.87 (m, 2H), 8.48(s, 1H).

Example 7 N-(4-Methoxyphenyl) (4-trifluoromethyl)benzaldimine

White needles; mp 124° C.; ¹ H NMR (CDCl₃) δ3.81 (s, 3H), 6.91 (d, J=8.8Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 8.10 (d, J=8.6Hz, 2H), 8.39 (s,1H).

Example 8 N-(4-Methoxyphenyl)furfuraldimine

Yellow pellets; mp 68°-70° C.; ¹ H NMR (CDCl₃) δ3.82 (s, 3H), 6.54 (dd,J=3.5, 1.8 Hz, 1H), 6.90 (d, J=3.5 Hz, 1H), 6.92 (d, J=8.9 Hz, 2H), 7.26(d, J=8.9 Hz, 2H), 7.59 (d, J=1.8 Hz, 1 H), 8.31 (s, 1 H).

Example 9 N-(4 -Methoxyphenyl)-3 -phenylpropenaldimine

Yellow leaves; mp 119°-121° C.; ¹ H NMR (CDCl₃) δ3.81 (s, 3H), 6.90-7.60(m, 7H), 8.28 (m, 1H) (ca. 1:1 mixture of stereoisomers).

Example 10 N-(4 -Methoxyphenyl)-3 -(2 -furyl)propenaldimine

Yellow needles; mp 71°-73° C.; ¹ H NMR (CDCl₃) δ3.78 (s, 3H), 6.45 (dd,J=3.4, 1.6 Hz, 1H), 6.52 (d, J=3.4 Hz, 1H), 6.87 (d, J=15.8 Hz, 1H),6.90 (d, J=8.9 Hz, 2H), 6.98 (dd, J=15.8, 8.7 Hz, 1H), 7.18 (d, J=8.9Hz, 2H), 7.46 (d, J=1.6 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H).

Example 11 N-(4-Methoxyphenyl)-3-methylbutanaldimine

Yellow oil; ¹ H NMR (CDCl₃) δ1.02 (d, J=6.7 Hz, 6H), 2.03 (m, 1H), 2.33(dd, J=6.9, 5.3 Hz, 2H), 3.78 (s, 3H), 6.86 (d, J=8.8 Hz, 2H), 7.03 (d,J=8.8 Hz, 2H), 7.86 (t, J=5.3 Hz, 1H).

Example 12 N-(4-Methoxyphenyl)cyclohexylacetaldimine

Yellow oil; ¹ H NMR (CDCl₃) δ1.00-1.80 (m, 11H), 2.34 (dd, J=6.7, 5.4Hz, 2H), 3.79 (s, 3H), 6.86 (d, J=8.9 Hz, 2H), 7.02 (d, J=8.9 Hz, 2H),7.86 (t, J=5.4 Hz, 1H); IR (neat) 3033-2849, 1505, 1244, 1038, 803 cm⁻¹.

Chiral enolate-imine cyclocondensation reactions were run to obtain the4-substituted-2-azetidinones (VI) and (VI') shown in Scheme 1. Otherazetidinones having different substituents for R¹ were prepared byfollowing the same procedures set forth in Examples 13 and 15. Theidentification data for these azetidinones is shown in Examples 14 and16-20, respectively.

Examples 13-14 Preparations of(3R,4S)-3-silyloxy-4-substituted-2-azetidinones (VI)

A typical procedure is described for the preparation of(3R,4S)-3-triisopropylsilyloxy-4-phenyl-2-azetidinone (VIa). To asolution of 645 μL (4.6 mmol) of diisopropylamine in 10 mL of THF, wasadded 1.85 mL (4.6 mmol, 2.5M) of n-butyllithium at 0° C. The solutionwas stirred 1 h at 0° C. followed by the addition of 1.5 g (3.8 mmol) of(-) TIPS ester in 15 mL of THF over a 1 hour period (using a cannula) at-78° C. The reaction was stirred 2 hours at this temperature followed bythe addition of 817 mg (4.6 mmol) of N-trimethylsilyl benzaldimine in 15mL of THF over a 2 h period at -95° C. The reaction was stirredovernight at this temperature and allowed to slowly warm up at roomtemperature. The reaction was quenched by addition of saturated NH₄ Cl.The aqueous layer was extracted with ether. The organic layer was washedwith 3% HCl and brine, dried over MgSO₄ and concentrated. The crude oilwas purified by chromatography on silica gel using 1:5 EtOAc/hexanes asthe eluent to give 1.03 g (84%) of(3R,4S)-3-Triisopropylsilyloxy-4-phenyl-2-azetidinone (VIa) as a whitesolid.

Identification data for (VIa) are shown below:

Mp 76°-77° C.; [α]_(D) ²⁰ +52.7° (C 1.00, CHCl₃); ¹ H NMR (300 MHz,CDCl₃) δ0.86-0.93 (m, 21H), 4.81 (d, J=4.7 Hz, 1H), 5.17 (dd, J=4.7, 2.6Hz, 1H), 6.18 (bs, 1H), 7.17-7.35 (m, 5H); ¹³ C NMR (75 MHz, CDCl₃)δ11.8, 17.4, 17.5, 59.6, 79.9, 127.9, 128.0, 128.1, 136.4, 170.0; IR(KBr) 3234, 2946-2866, 1760, 1458 cm⁻¹. Anal. Calcd for C₁₈ H₂₉ NO₂ Si:C 67.66; H 9.15; N 4.38. Found: C 67.64; H 9.25; N 4.44.

Example 14 (3R,4S)-3-Triisopropylsilyloxy-4-(2-phenylethenyl)-2-azetidinone (VIb)

72%; colorless liquid; ¹ H NMR (300 MHz, CDCl₃) δ0.98-1.02 (m, 21H),4.36 (dd, J=4.6, 8.3 Hz, 1H), 5.09 (dd, J=2.3, 4.6 Hz, 1H), 6.29 (dd,J=8.3, 16.0 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.83, (bs, 1H), 7.23-7.39(m, 5H); ¹³ C NMR (75 MHz, CDCl₃) δ11.79, 17.61, 17.66, 58.34, 79.86,126.05, 126.45, 127.90, 128.56, 134.41, 136.30, 169.69; IR (neat) 3262,3032, 2944, 2865, 1748, 1672, 1623 cm⁻¹. Anal. Calcd for C₂₀ H₃₁ NO₂ Si:C, 69.52; H, 9.04; N, 4.05. Found: C, 69.75; H, 9.02; N, 3.89.

Examples 15-20 Preparations of(3R,4S)-1-(4-methoxyphenyl)-3-silyloxy-4-substituted-2-azetidinones(VI')

To a solution of 2.51 mmol of diisopropylamine in 15 mL of THF was added2.51 mL of n-butyllithium (2.5M in THF) at -10° C. After 30 min, lithiumdiisopropylamide (LDA) was generated and the solution was cooled to -95°C. A solution of 2.17 mmol of chiral ester in 5 mL of THF was added.After 1 hr, a solution of 2.5 mmol of the appropriate imine in 3 mL ofTHF was added. The mixture was stirred at -95° C. overnight, and theprogress of the reaction was monitored by TLC or ¹ H NMR. The reactionwas quenched with saturated NH₄ Cl and THF was removed using a rotaryevaporator. Ether (10 mL) was added and the aqueous layer was extractedwith ether (10 mL×3). Drying and removal of the solvent gave the crudeproduct which was purified by silica gel column chromatography(hexane/ethyl acetate=10:1) to afford the corresponding pure β-lactam.The enantiomeric excess was determined by HPLC using a CHIRALCEL ODcolumn using n-hexane/isopropyl alcohol (i-PrOH) (90/10) as the eluant.

Example 15(3R,4S)-4-(isobutyl)-1-(4-methoxyphenyl)-3-triisopropylsilyloxy-2-azetidinone(VI'-c)

87%; pale yellow solid; mp 59°-60 ° C.; [α]_(D) ²⁰ +60.46° (c 1.26,CHCl₃); ¹ H NMR (300 MHz, CDCl₃) δ0.96 (d, J=6.4 Hz, 3H), 1.03 (d, J=6.4Hz, 3H), 1.10-1.30 (m, 21H), 1.60-1.68 (m, 1H), 1.70-1.92 (m, 2H), 3.75(s, 3H), 4.16-4.22 (m, 1H), 5.06 (d, J=5.1 Hz, 1H), 6.86 (d, J=9.0 Hz,2H), 7.32 (d, J=9.0 Hz, 2H); ¹³ C NMR (75 MHz, CDCl₃) δ12.34, 17.82,17.91, 22.18, 23.37, 25.34, 35.89, 55.50, 57.33, 76.34, 114.52, 118.73,131.00, 156.29, 165.58; IR (KBr) 2946, 1742, 1513, 1458, 1249 cm¹. Anal.Calcd for C₂₃ H₃₉ NO₃ Si: C, 68.10; H, 9.70; N, 3.45. Found: C, 68.26;H, 9.85; N, 3.35.

Example 16(3R,4S)-4-(Cyclohexylmethyl)-1-(4-methoxyphenyl)-3-triisopropylsilyloxy-2-azetidinone(VI'-d)

83% low melting point solid; [α]_(D) ²⁰ +43.7° (c 0.92, CHCl₃); ¹ H NMR(300 MHz, CDCl₃) δ0.85-1.95 (m, 34H), 3.78 (s, 3H), 4.19-4.25 (m, 1H),5.05 (d, J=5.1 Hz, 1H), 6.86 (d, J=9.0 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H);¹³ C NMR (75 MHz, CDCl₃) δ12.15, 17.76, 17.83, 26.12, 26.22, 26.47,32.84, 34.22, 34.51, 55.36, 56.41, 76.13, 114.30, 118.45, 130.81,155.99, 165.55; IR (neat) 2925-2865, 1749, 1513, 1464, 1448, 1389, 1246,1174, 1145, 1128, 939, 882, 828, 684 cm⁻¹. Anal. Calcd for C₂₆ H₄₃ NO₃Si: C, 70.06; H, 9.72; N, 3.14. Found: C, 69.91; H, 9.71; N, 3.02.

Example 171-(4-Methoxyphenyl)-3-triisopropylsilyloxy-4-(4-fluorophenyl)-2-azetidinone (VI'-f)

White solid; mp 121°-122° C.; [α]_(D) ²⁰ +82.5° (c 0.724, CHCl₃); ¹ HNMR (CDCl₃) δ0.82-0.84 (m, 18H), 0.86-1. 01 (m, 3H), 3.62 (s, 3H), 5.02(d, J=4.9 Hz, 1H), 5.11 (d, J=4.9 Hz, 1H), 6.68 (d, J=6.9 Hz, 2H),6.96-7.25 (m, 6H); IR (CHCl₃) 3050, 2974, 2868, 1748 cm⁻¹. Anal. Calcdfor C₂₅ H₃₄ NO₃ FSi: C, 67.69; H, 7.72; N, 3.16. Found: C, 67.77; H,7.83; N, 3.19.

Example 181-(4-Methoxyphenyl)-3-triisopropylsilyloxy-4(4-trifluoromethylphenyl)-2-azetidinone(VI'-g)

White solid; mp 132°-133° C.; [α]_(D) ²⁰ +89.7° (c 0.925, CHCl₃); ¹ HNMR (CDCl₃) δ0.87-1.15 (m, 21H), 3.74 (s, 3H), 5.21 (d, J=4.9 Hz, 1H),5.27 (d, J=4.9 Hz, 1H), 6.79 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H),7.46 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H); IR (CHCl₃) 3050, 2975,2868, 1750, 878 cm⁻¹. Anal. Calcd for C₂₀ H₃₄ NO₃ F₃ Si: C, 63.26; H,6.94; N, 2.84. Found: C, 63.36; H, 7.13; N, 2.88.

Example 19 1-(4-Methoxyphenyl)-3-triisopropylsilyloxy-4-(2-furyl)-2-azetidinone (VI '-h)

White solid; mp 109°-110° C.; [α]_(D) ²⁰ -86.2° (C 1.4, CHCl₃); ¹ H NMR(CDCl₃) δ0.98-1.10 (m, 21H), 3.75 (s, 3H), 5.20 (d, J=4.9 Hz, 1H), 5.24(d, J=4.9 Hz, 1H), 6.35-6.40 (m, 2H), 6.81 (d, J=9.0 Hz, 2H), 7.30 (d,J=9.0 Hz, 2H), 7.42 (m, 1H); ¹³ C NMR (CDCl₃) δ11.96, 17.52, 17.57,55.43, 57.19, 78.13, 110.23, 110.63, 114.44, 118.55, 131.08, 142.80,148.51, 156.45, 165.27. Anal. Calcd for C₂₃ H₃₃ NO₄ Si: C, 66.47; H,8.00; N, 3.37. Found: C, 66.56; H, 8.13; N, 3.30.

Example 201-(4-Methoxyphenyl)-3-triisopropylsilyloxy-4-{2-(2-furyl)ethenyl}-2-azetidinone(VI'-i)

White solid; mp 103.5°-105.5° C.; [α]_(D) 20-128.4° (c 2.8, CHCl₃); ¹ HNMR (CDCl₃) δ1.05-1.09 (m, 21H), 3.76 (s, 3H), 4.69 (dd, J=4.9, 8.6 Hz,1H), 5.15 (d, J=4.9 Hz, 1H), 6.25 (dd, J=8.6, 16.0 Hz, 1H), 6.29 (d,J=3.3 Hz, 1H ), 6.37 (dd, J=1.8, 3.3 Hz, 1H), 6.57 (d, J=16.0 Hz, 1H)6.83 (m, 2H), 7.34-7.41 (m, 3H); ¹³ C NMR (CDCl₃) δ12.11, 17.70, 17.74,55.54, 61.94, 77.18, 78.45, 107.88, 108.42, 111.26, 114.54, 118.70,123.46, 123.82, 142.46, 190.99; IR (KBr) 2948, 2866, 1743, 1513, 1389,1246, 1181, 1120 cm⁻¹. Anal. Calcd for C₂₅ H₃₅ NO₄ Si: C, 67.99; H,7.99; N, 3.17. Found: C, 68.07; H, 7.94; N, 3.10.

The transformation of β-lactam intermediates (VI') to β-lactams (VI) asshown in Scheme 1 was accomplished by methods discussed in Examples21-23. Azetidinones obtained in this manner, (VIc) to (VIj), exemplifydifferent R¹ groups. Identification data for (VIc) to (VIj) are shownnext to each compound.

Examples 21-23 Transformation of N-(4-methoxyphenyl)-β-lactams (VI') toβ-lactams (VI)

To a solution of 0.24 mmol of 1-(4-methoxyphenyl)-β-lactam in MeCN (20mL) was added 0.65 mmol of cerium ammonium nitrate (CAN) in 10 mL CH₃ CNand 20 mL of water in 20 min at -15° C. After stirring for 1 hour, itwas diluted with water (20 mL), and the mixture was then extracted withethyl acetate (15 mL×2). The combined organic layer was washed withwater (7 mL), 5% Na₂ SO₄ (10 mL×2), 5% Na₂ CO₃ (10 mL) and brine (5 mL)in sequence. Drying, removal of the solvent in vacuo followed bydecolorization with activated charcoal afforded the crude product. Thisproduct was further purified by silica gel column chromatography usinghexanes/ethyl acetate, 3/1 eluent to furnish N-deprotected β-lactam.

Example 21 (3R,4S)-4-(isobutyl)-3-triisopropylsilyloxy-2-azetidinone(VIc)

83%; yellow oil; [α]_(D) ²⁰ +35.45° (c 1.33, CHCl₃); ¹ H NMR (300 MHz,CDCl₃) δ0.93 (d, J=6.6 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H), 1.05-1.25 (m,22H), 1.52 (m, 1H), 1.67 (m, 1H), 3.78 (m, 1H), 4.96 (dd, J=4.8, 2.4 Hz,1H), 6.02 (bs, 1H); ¹³ C NMR (75 MHz, CDCl₃) δ12.12, 17.72, 17.80,22.29, 23.08, 25.35, 39.08, 54.45, 78.04, 170.00; IR (neat) 3238, 1759,1465, 1184 cm⁻¹. Anal. Calcd for C₁₆ H₃₃ NO₂ Si: C, 64.16; H,11.1; N,4.68. Found: C, 64.17; H, 10.96; N, 4.47.

Example 22(3R,4S)-4-(Cyclohexylmethyl)-3-triisopropylsilyloxy-2-azetidinone (VId)

85%; yellow oil; [α]_(D) ²⁰ +12.44° (c 1.46, CHCl₃); ¹ H NMR (300 MHz,CDCl₃) δ0,97-1.25 (m, 32H), 1.40-1.70 (m, 2H), 3.80 (dt, J=8.4, 4.8 Hz,1H), 4.95 (dd, J=4.8, 2.4 Hz, 1H), 6.05 (bs, 1H); ¹³ C NMR (75 MHz,CDCl₃) δ12.06, 17.77, 17.82, 26.16, 26.25, 26.46, 33.15, 33.82, 34.85,37.72, 53.89, 77.98, 169.98; IR (neat) 3238, 1759, 1465, 1184 cm⁻¹.Anal. Calcd for C₁₉ H₃₇ NO₂ Si: C, 67.20; H, 10.98; N, 4.12. Found: C,67.40; H, 10.79; N, 3.98.

Example 23 preparation of (3R,48)-3-Triisopropylsilyloxy-4-(2-cyclohexylethyl)-2-azetidinone (VIj)

A mixture of (VIb) (100 mg, 0.29 mmol) in methanol (10 mL) and 5% Rh-Ccatalyst (10 mg) was hydrogenated at 50° C. and 800 psi of hydrogen for20 hours. After the catalyst was filtered out and the solventsevaporated in vacuo, the residue was purified on a short silica gelcolumn using hexane/ethyl acetate (5/1) as the eluant to give 95 mg (93%yield) of VIj as a colorless liquid: [α]_(D) ²⁰ -162.3° (c 1.46 CHCl₃);¹ H NMR (CDCl₃) δ1.07-1.72 (m, 36H), 3.61-3.67 (m, 1H), 4.94 (dd, J=2.4,4.8 Hz, 1H), 6.42 (bs, 1H); ¹³ C NMR (CDCl₃) δ12.02, 17.79, 26.31,26.60, 27.54, 33.19, 33.39, 33.54, 37.71, 56.44, 77.74, 170.15; IR(neat) 3236 ('NH), 2925, 2866, 1760 ('CO), 1464, 1451, 1384, 1348, 1244cm⁻¹. Anal. Calcd for C₂₇ H₃₉ NO₃ Si: C, 71.48; H, 8.66; N, 3.09. Found:C, 71.35; H, 8.66; N, 3.01.

The conversion of 3-TIPSO-4-substituted-2-azetidinones or β-lactams VIto β-lactams VII as shown in Scheme 2 is accomplished by methods ofpreparations discussed in Examples 24-28. Identification data for eachβ-lactam (VIIa)-(VIIe) follow each compound.

Examples 24-28 Preparation of 3-hydroxy-4-substituted-2-azetidinones(VII)

To a solution of 2.6 mmol of3-triisopropylsilyloxy-4-substituted-2-azetidinone in 20 mL of THF, wasadded at room temperature. 3.1 mmol (1M in THF) of n-butyl fluoride(NBu₄ F). After 5 h, the solvent was evaporated and the crude oil wasdirectly purified by chromatography on silica gel using 5:1EtOAc/hexanes eluent to afford of 3-hydroxy-4-substituted-2-azetidinone:

Example 24 (3R,4S)-3-Hydroxy-4-phenyl-2-azetidinone (VIIa)

100%; white solid; mp 189°-190° C.; [α]_(D) ²⁰ +181.6° (c 0.5, CH₃ OH);¹ H NMR (300 MHz, CD₃ OD) δ4.84 (d, J=4.7 Hz, 1H), 5.04 (d, J=4.7 Hz,1H), 7.25-7.35 (m, 5H); IR (KBr) 3373, 3252, 1732, 1494 cm⁻¹. Anal.Calcd for C₉ H₉ NO₂ : C 66.25%, H 5.56%, N 8.58% Found: C 66.42% H 5.74%N 8,62%.

Example 25 (3R, 4S)-3-Hydroxy-4 -(2-phenylethenyl)-2-azetidinone (VIIb)

82%; white solid; mp 143°-144° C.; [α]_(D) ²⁰ +21.9° (c 1.05, MeOH); ¹ HNMR (300 MHz, CD₃ OD) δ4.35 (ddd, J=0.8, 4.7, 7.7 Hz, 1H), 4.93 (d,J=4.7 Hz, 1H), 6.28 (dd, J=7.7, 16.0 Hz, 1H), 7.18-7.43 (m, 5H); ¹³ CNMR (75 MHz, CD₃ OD) δ58.95, 79.63, 126.83, 127.58, 128.88, 129.61,135.28, 137.96, 172.79; IR (KBr) 3320, 3276, 1754, 1464 cm⁻¹. Anal.Calcd for C₁₁ H₁₁ NO₂ : C, 69.83; H, 5.86; N, 7.40. Found: C, 69.72; H,5.92; N, 7.24.

Example 26 (3R, 4S)-3-Hydroxy-4-(isobutyl)-2-azetidinone (VIIc)

94%; white solid; mp 141°-142° C; [α]_(D) ²⁰ +26.6° (c 0.70, MeOH); ¹ HNMR (300 MHz, MeOH-d₄) δ0.94 (d, J=6.8 Hz 3H), 0.97 (d, J=6.8 Hz, 3H),1.45 (m, 2H), 1.71 (sept, J=6.6 Hz, 1H), 3.75 (m, 1H), 4.79 (d, J=4.7Hz, 1H); ¹³ C NMR (75 MHz, MeOH-d₄) δ22.62, 23.48, 26.53, 39.90, 55.47,77.76, 173.18; IR (KBr) 3274, 3178, 1762, 1685, 1155 cm⁻¹. Anal. Calcdfor C₇ H₁₃ NO₂ : C, 58.72; H, 9.15; N, 9.78. Found: C, 58.55; H, 9.41;N, 9.69.

Example 27 (3R, 4S)-4-(Cyclohexylmethyl)-3-hydroxy-2-azetidinone (VIId)

92%; white solid; mp 147°-148° C.; [α]_(D) ²⁰ +8.73° (c, 0.573, CH₃ OH);¹ H NMR (300 MHz, MeOH-d₄) δ0.88-1.82 (m, 13H), 3.78 (m, 1H), 4.79 (d,J=4.7 Hz, 1H); ¹ H NMR (300 MHz, DMSO-d₆) δ0.86-1.72 (m, 13H), 3.58 (m,1H), 4.63 (m, 1H), 5.82 (d, J=7.6 Hz, 1H), 8.13 (d, J=5.6, 1H); ¹³ C NMR(75 MHz, MeOH-d₄) δ27.29, 27.41, 27.48, 34.07, 35.06, 36.11, 38.52,55.02, 77.65, 173.22; IR (KBr) 3301, 3219, 2915, 2847, 1754, 1694, 1168cm⁻¹. Anal. Calcd for C₁₀ H₁₇ NO₂ : C, 65.54, H, 9.35, N, 7.64. Found:C, 65.72, H, 9.46, N, 7.42.

Example 28 3R,4S)-4-cyclohexyl-3-hydroxy-2-azetidinone (VIIe)

A suspension of 500 mg (3.06 mmol) of 4-phenyl-3-hydroxy-2-azetidinoneVIa and 15 mg of Rh-C in 10 mL of methanol was heated at 90° C. under800 psi in an autoclave. After 5 days, the hydrogen pressure wasreleased and the catalyst filtered on celite. Evaporation of the solventafforded a solid which was recrystallized in ethyl acetate to give 440mg (85%) of VIIe as a white solid: White solid; mp 140°-140.5° C.;[α]_(D) ²⁰ +65.1° (C 0.66, CH₃ OH); ¹ H NMR (250 MHz, MeOH-d₄)δ0.75-1.10 (m, 2H), 1.12-1.35 (m, 3H), 1.40-2.00 (m, 6H), 3.28 (dd,J=9.7, 4.6 Hz, 1H), 4.81 (d, J=4.6 Hz, 1H); ¹ H NMR (250 MHz, DMSO-d₆)δ0.75-1.00 (m, 2H), 1.10-1.35 (m, 3H), 1.37-1.55 (m, 1H), 1.58-1.85 (m,5H), 3.10 (dd, J=9.6, 4.7 Hz, 1H), 4.67 (m, 1H), 5.87 (d, J=7.8 Hz, 1H),8.21 (bs, 1H); ¹³ C NMR (63 MHz, DMSO-d₆) δ25.08, 25.36, 26.07, 28.83,29.17, 37.51, 59.04, 76.41, 170.21; IR (KBr) 3312, 3219, 2928, 1726cm⁻¹. Anal. Calcd for C₉ H₁₅ NO₂ : C, 63.88, H, 8.93, N, 8.28. Found: C,63.70, H, 9.00, N, 8.06.

Once formed, β-lactams (VII) required protection at the hydroxyl group.The protecting groups were attached by methods described in Examples29-33 to yield β-lactams (VI). The identification data for β-lactams(VI) protected by different G groups are shown after each compound(VIa-EE) to (VIe-EE).

Examples 29-33 Preparation of3-(hydroxy-protected)-4-substituted-2-azetidinones (VI)

To a solution of 1.9 mmol of 3-hydroxy-4-substituted-2-azetidinone in 20mL of THF, was added at 0° C. 3.9 mmol of ethyl vinyl ether. After 2hours, at 0° C. the reaction mixture was diluted with ether and washedwith saturated NaHCO₃. The organic layer was dried over Na₂ CO₃,filtered and concentrated to yield of3-(1-ethoxyethoxy)-4-substituted-2-azetidinone:

Example 29 (3R, 4S)-3 -(1-Ethoxyethoxy)-4-phenyl-2-azetidinone (VIa-EE)

100%; white solid; mp 78°-80° C.; ¹ H NMR δ(CDCl₃) [0.98 (d, J=5.4 Hz),1.05 (d, J=5.4 Hz), 3H], [1.11 (t, J=7.1 Hz), 1.12 (t, J=7.1 Hz), 3H],[3.16-3.26 (m), 3.31-3.42 (m), 3.59-3.69 (m), 2H], [4.47 (q, J=5.4 Hz),4.68 (q, J=5.4 Hz), 1H], [4.82 (d, J=4.7 Hz), 4.85 (d, J=4.7 Hz), 1H],5.17-5.21 (m, 1H), 6.42 (bd, 1H), 7.35 (m, 5H); IR (KBr) 3214, 2983,2933, 1753, 1718, 1456 cm⁻¹. Anal. Calcd for C₁₃ H₁₇ NO₃ : C, 66.36; H,7.28; N, 5.95. Found: C, 66.46; H, 7.11; N, 5.88.

Example 30(3R,4S)-3-1(Ethoxyethoxy)-4-(2-phenylethenyl)-2-azetidinone(VIb-EE)

98%; white solid; mp 98°-99° C.; ¹ H NMR (300 MHz, CDCl₃) δ[1.17 (t,J=7.1 Hz), 1.18 (t, J=7.1 Hz), 3H], [1.26 (d, J=5.4 Hz), 1.35 (d, J=5.4Hz), 3H], [3.44-3.52 (m), 3.60-3.68 (m), 3.75-3.82 (m), 2H], 4.41 (dd,J=4.9, 8.5 Hz, 1H), [4.81 (q, J=5.4 Hz), 4.90 (q, J=5.4 Hz), 1H], [5.11(d, J=4.9 Hz), 5.11 (d, J=4.9 Hz), 1H], 6.01 (bs, 1H), [6.27 (dd, J=8.5,15.9 Hz), 6.28 (dd, J=8.5, 15.9 Hz), 1H], [6.61 (d, J=15.9 Hz), 6.63 (d,J=15.9 Hz), 1H], 7.27-7.42 (m, 5H); ¹³ C NMR (75 MHz, CDCl₃) δ15.04,20.37, 20.42, 57.22, 57.81, 61.23, 62.22, 78.77, 79.29, 99.50, 99.82,125.56, 125.79, 126.59, 128.12, 128.65, 134.47, 134.58, 136.15, 168.59,168.77; IR (KBr) 3310, 3030, 2963, 1770 cm⁻¹. Anal. Calcd for C₁₅ H₁₉NO₃ : C, 68.94; H, 7.33; N, 5.36. Found: C, 69.13; H, 7.44; N, 5.16.

Example 31 (3R,4S)-3-(1-Ethoxyethoxy)-4-(isobutyl)-2-azetidinone(VIc-EE)

100% colorless oil: [α]_(D) ²⁰ +20.93° (c 1.72, CHCl₃); ¹ H NMR (300MHz, CDCl₃) δ0.86 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H), 1.17 (t,J=7.0 Hz, 3H), [1.29 (d, J=5.3 Hz), 1.34 (d, J=5.3 Hz), 3H], 1.46 (m,2H), 1.62 (m, 1H), [3.49 (m), 3.69 (m), 2H)], 3.80 (m, 1H), [4.79 (q,J=5.4 Hz), 4.90 (q, J=5,4 Hz), 1H], 4.87 (m, 1H), 6.78 (bs, 1H); ¹³ CNMR (75 MHz, CDCl₃) δ15.08, 20.42, (21.98, 22.06), (23.15, 23.22),25.35, (39.01, 39.10), (53.35, 53.69), (61.24, 62.24), (77.79, 77.92),(99.75, 100.05), (169.56, 169.65); IR (neat) 3269, 2956, 2871, 1758,1468, 1382, 1340, 1152, 1115, 1083, 1052, 936, 893 cm⁻¹.

Example 32 (3R,4S)-4-(Cyclohexylmethyl)-3-(1-ethoxyethoxy)-2-azetidinone(VId-EE)

100%; colorless oil; [α]_(D) ²⁰ +10.92° (c 1.42, CHCl₃); ¹ H NMR (300MHz, CDCl₃) δ0.84-1.71 (m, 13H), 1.16 (t, J=7.0 Hz, 3H), [1.28 (d, J=5.3Hz), 1.33 (d, J=5.3 Hz), 3H], 3.48 (m, 1H), [3.72 (m), 3.8 (m), 2H],[4.78 (q, J=5.4 Hz), 4.85 (q, J=5.4 Hz), 1H], 4.82 (m, 1H), 6.76 (bs,1H); ¹³ C NMR (75 MHz, CDCl₃) δ14.37, 19.72, 25.30, 25.44, 25.63,(32.02, 32.13), (33.09, 33.17), (34.03, 34.07), (36.98, 37.07), (52.15,52.49), (60.49, 61.52), (75.97, 76.39), (99.00, 99.35), (168.98,169.05); IR (neat) 3278, 2924, 2852, 1758, 1448, 1382, 1150, 1114, 1086,938, 886 cm⁻¹. Anal. Calcd for C₁₄ H₂₅ NO₃ : C,65.85; H, 9.87; N, 5.49.Found: C, 66.03; H, 9.71; N, 5.30.

Example 33 (3R,4S)-4-Cyclohexyl-3-(1-ethoxyethoxy)-2-azetidinone(VIe-EE)

100%; white solid; mp 87°-89° C.; [α]_(D) ²⁰ +83° (c 0.76, CH₃ OH); ¹ HNMR δ (250 MHz, CDCl₃) 0.84 (m, 2H), 1.07-1.34 (m, 9H), 1.66 (m, 6H),3.32 (m, 1H), [3.42 (q, J=7.7 Hz), 3.54 (q, J=7.7 Hz), 3.65 (q, J=7.7Hz), 3.74 (q, J=7.7 Hz), 2H], 4.81 (m, 1H), [4.80 (m), 4.90 (q, J=5.2Hz), 1H], 6.92 (bs, 1H); IR (CHCl₃) 3412, 2989, 2931, 1760, 1443, 1155,1114 cm⁻¹. Anal. Calcd for C₁₃ H₂₇ NO₃ : C, 64.70; H, 9.61; N, 5.80.Found: C, 64.82; H, 9.66; N, 5.64.

Protected β-lactams (VI) in which G represents protecting groupsdescribed elsewhere in the specification were reacted with acylchlorides, chloroformates or carbamoyl chlorides in the presence of abase according to preparation methods described in Examples 34 to 52.The resulting β-lactams obtained in Examples 34 to 52 are shown inScheme 2. Identification data for β-lactams (Va) to (Vd) in which Grepresents different protecting groups are listed after each β-lactamfollowing each example.

Example 34 Preparations of1-acyl-3-(hydroxy-protected)-4-substituted-2-azetidinones (Va)

A typical procedure is described for the preparation of(3R,4S)-1-benzoyl-3-(ethoxylethoxy)-4-phenyl-2-azetidinone (Va-EE). To asolution of VIa-EE (460 mg, 1.9 mmol), 4(dimethylamino)pyridine DMAP (5mg), and triethylamine (542 mL, 3.9 retool) in 20 mL of dichloromethane,was added dropwise benzoyl chloride (340 mL, 2.9 mmol) at 0° C. withstirring. The cooling bath was removed and the mixture was stirred at25° C. for 2 h. The reaction mixture was washed with saturated aqueousNH₄ Cl and brine, dried over anhydrous Na2CO₃ and concentrated in vacuoto give the oily crude product. The crude product was purified through ashort silica gel column (eluant: EtOAc/hexanes=1/5) to afford pure Va-EE(611 mg, 92%) as a colorless oil: IR (neat) 3064-2933, 1798, 1682, 1450cm⁻¹ ; ¹ H NMR (CDCl₃) δ[1.04 (d, J=5.4 Hz), 1.14 (d, J=5.4 Hz)] (3H),1.11-1.17 (m, 3H), 3.23-3.74 (m, 2H), [4.57 (q, J=5.4 Hz) , 4.76 (q,J=5.4 Hz)] (1H), 5.28 (d, J=6.2 Hz, 1H), [5.43 (d, J=6.2 Hz), 5.46 (d,J=6.2 Hz )] (1H), 7.30-7.65 (m, 8H).

Examples 35-46 Preparations of 1-alkoxy- and1-aryloxy-carbonyl-3-(hydroxy-protected)-4-substituted-2-azetidinones(Vb)

To a solution of 2.2 mmol of3-(1-ethoxyethoxy)-4-substituted-2-azetidinone, 5 mg of DMAP, 4.5 mmolof triethylamine in 20 mL of dichloromethane, was added dropwise at 0°C. 3.3 mmol of alkyl chloroformate dissolved in 5 mL of dichloromethane.The reaction mixture was stirred overnight at room temperature. Theorganic layer was washed several times with brine, dried over Na₂ CO₃and concentrated. The crude solid was purified by chromatography onsilica gel to yield N-protected β-lactam:

Example 35(3R,4S)-1-Methoxycarbonyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone(Vb-a-EE)

62%; pale yellow oil; [α]_(D) ²⁰ +98.2° (c 1.1, CHCl₃); ¹ H NMR (250MHz, CDCl₃) δ[0.97 (d, J=5.4 Hz), 1.08 (d, J=5.4 Hz), 3H], 1.10 (bt,J=7.3 Hz, 3H), [3.21 (dq, J=9.5, 7.1 Hz), 3.32 (q, J=7.1 Hz), 3.64 (dq,J=9.5, 7.1 Hz), 2H], [3.76 (s), 3.77 (s), 3H], [4.48 (q, J=5.4 Hz), 4.69(q, J=5.4 Hz), 1H], [5.11 (d, J=5.9 Hz), 5.14 (d, J=5.9 Hz), 1H], 5.23(d, J=5.9 Hz, 1H), 7.34 (m, 5H); ¹³ C NMR (63 MHz, CDCl₃) δ (14.96,15.07), (19.84, 20.69), 53.59, (60.74, 62.36), (61.14, 61.92), (76.21,77.21), (99.16, 99.56), (127.73, 128.03, 128.31, 128.36, 128.62,128.85), (133.41, 133.58), (149.51, 149.57), (165.21, 165.67); IR (neat)3033, 2979, 2957, 1821, 1738, 1654, 1440, 1336, 1101 cm⁻¹. Anal. Calcdfor C₁₅ H₁₉ NO₅ : C, 61.42; H, 6.53; N, 4.78. Found: C, 61.55; H, 6.51;N, 4.90.

Example 36(3R,4S)-1-Ethoxycarbonyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone(Vb-b-EE)

82%; colorless oil; [α]_(D) ²⁰ +100.9° (c 1.08, CHCl₃); ¹ H NMR (250MHz, CDCl₃) δ [0.95 (d, J=5.4 Hz), 1.06 (d, J=5.4 Hz), 3H], 1.08 (bt,J=7.3 Hz, 3H), [1.19 t, J=7.1 Hz), 1.20 (t, J=7.1 Hz), 3H], [3.20 (dq,J=9.4, 7.1 Hz), 3.31 (q, J=7.1 Hz), 3.32 (q, J=7.1 Hz), 3.63 (dq, J=9.4,7.1 Hz), 2H], [4.18 (q, J=7.1 Hz), 4.19 (q, J=7.1 Hz), 2H], [4.47 (q,J=5.4 Hz), 4.67 (q, J=5.4 Hz), 1H], [5.09 (d, J=5.8 Hz), 5.13 (d, J=5.8Hz), 1H], 5.21 (d, J=5.8 Hz, 1H), 7.30 (m, 5H); ¹³ C NMR (63 MHz, CDCl₃)δ14.14, (14.95, 15.07), (19.86, 20.05), (60.76, 62.35), 62.36, (61.14,61.90), (76.18, 77.20), (99.17, 99.53), (127.73, 128.02, 128.25, 128.30,128.50, 128.63), (133.59, 133.77), (148.99, 149.05), (165.33, 165.79);IR (neat) 2978, 2934, 1814, 1731, 1646, 1540, 1456, 1323, 1175, 1096cm⁻¹. Anal. Calcd for C₁₆ H₂₁ NO₅ : C, 62.53; H, 6.89; N, 4.56. Found:C, 62.45; H, 6.63; N, 4.83.

Example 37(3R,4S)-1-n-Butoxycarbonyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone(Vb-c-EE)

83%; colorless oil; [α]_(D) ²⁰ +70.4° (c 1.25, CHCl₃); ¹ H NMR (250 MHz,CDCl₃) δ0.79 (t, J=7.3 Hz, 3H), [0.94 (d, J=5.1 Hz), 1.07 (d, J=5.1 Hz),3H], 1.07 (t, J=7.4 Hz, 3H), 1.20 (m, 2H), 1.51 (quint, J=6.7 Hz, 2H),[3.21 (m), 3.30 (q, J=7.1 Hz), 3.61 (m), 2H], 4.09 (m, 2H), [4.46 (q,J=5.2 Hz), 4.66 (q, J=5.2 Hz), 1H], [5.07 (d, J=5.8 Hz), 5.11 (d, J=5.8Hz), 1H], 5.19 (d, J=5.8 Hz, 1H), 7.28 (m, 5H); ¹³ C NMR (63 MHz, CDCl₃)δ13.50, (14.95, 15.29), 18.71, (19.84, 20.05), 30.42, (60.77, 62.33),(61.25, 62.02), 66.51, (76.24, 77.26), (99.17, 99.52), (127.76, 128.03,128.22, 128.27, 128.50, 128.60), (133.61, 133.80), (148.96, 149.02),(165.40, 165.85); IR (neat) 2961, 2933, 1817, 1732, 1653, 1456, 1394,1250, 1099 cm⁻¹. Anal. Calcd for C₁₈ H₂₅ NO₅ : C, 64.46; H, 7.51; N,4.18. Found: C, 64.44; H, 7.57; N, 4.24.

Example 38(3R,4S)-1-tert-Butoxycarbonyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone(Vb-d-EE)

83%; white solid; mp 90°-91° C.; [α]_(D) ²⁰ +70.4° (c 1.25, CHCl₃); 1¹ HNMR (250 MHz, CDCl₃) δ [0.96 (d, J=5.4 Hz), 1.08 (d, J=5.4 Hz), 3H],[1.09 (t, J=7.0 Hz), 1.10 (t, J=7.0 Hz), 3H], [1.36 (s), 1.37 (s), 9H],[3.23 (dq, J=9.5, 7.1 Hz), 3.32 (q, J=7.1 Hz), 3.65 (dq, J=9.5, 7.1 Hz),2H], [4.48 (q, J=5.4 Hz), 4.69 (q, J=5.4 Hz), 1H], [5.03 (d, J=5.8 Hz),5.07 (d, J=5.8 Hz), 1H], 5.18 (d, J=5.8 Hz, 1H), 7.31 (m, 5H); ¹³ C NMR(63 MHz, CDCl₃) δ (14.98, 15.08), (19.89, 20.10), 27.84, (60.74, 62.32),(61.28, 62.08), (75.91, 76.54), (99.10, 99.41), (127.76, 128.07, 128.20,128.42, 128.85), (133.98, 134.16), 147.56, (165.61, 166.04); IR (CHCl₃)3025, 2982, 2932, 1809, 1725, 1601, 1497, 1331, 1256, 1125 cm⁻¹. Anal.Calcd for C₁₈ H₂₅ NO₅ : C, 64.46; H, 7.51; N, 4.18. Found: C, 64.50; H,7.41; N, 4.17.

Example 39(3R,4S)-3-(1-Ethoxyethoxy)-1-phenoxycarbonyl-4-phenyl-2-azetidinone(Vb-e-EE)

79%; white solid; mp 50°-52° C.; [α]_(D) ²⁰ +64.9° (C 0.94, CHCl₃); ¹ HNMR (250 MHz, CDCl₃) δ [1.00 (d, J=5.3 Hz), 1.11 (m), 3H], [1.14 (m),3H], [3.27 (m), 3.35 (q, ^(J=) 7.1 Hz), 3.70 (m), 2H], [4.54 (q, J=5.3Hz), 4.74 (q, J =5.3 Hz), 1H], [5.25 (d, J=5.8 Hz), 5.29 (d, J=5.8 Hz),1H], 5.34 (d, J=5.8 Hz, 1H), 7.03-7.39 (m, 10H); IR (CHCl₃) 3028, 2981,2934, 1815, 1744, 1591, 1486, 1327, 1192 cm⁻¹. Anal. Calcd for C₂₀ H₂₁NO₅ : C, 67.59; H, 5.96; N, 3.94. Found: C, 67.33; H, 6.06; N, 3.75.

Example 40 (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-1-phenylmethoxycarbonyl-2-azetidinone(Vb-f-EE)

44%; white solid; mp 58°-60° C.; [α]_(D) ²⁰ +91.4° (c 1.16, CHCl₃); ¹ HNMR (250 MHz, CDCl₃) δ [0.97 (d, J=5.3 Hz), 1.09 (d, J=5.3 Hz), 3H],[1.10 (t, J=7.0 Hz), 1.11 (t, J=7.0 Hz), 3H], [3.23 (dq, J=9.5, 7.1 Hz),3.33 (q, J=7.1 Hz), 3.66 (dq, J=9.5, 7.1 Hz), 2H], [4.50 (q, J=5.4 Hz),4.70 (q, J=5.4 Hz), 1H], [5.13 (d, J=5.6 Hz), 5.15 (d, J=5.6 Hz), 1H],[5.19 (s), 5.20 (s), 2H], 5.23 (d, J=5.6 Hz, 1H), 7.21 (m, 2H),7.26-7.37 (m, 8H); ¹³ C NMR (63 MHz, CDCl₃) δ (14.99, 15.10), (19.90,20.10), (60.83, 62.41), (61.64, 62.14), 68.01, (76.31, 77.28), (99.19,99.53), (127.37, 127.86, 128.07, 128.16, 128.36, 128.52, 128.63,128.85), (133.49, 133.68), 134.89, (148.72, 148.78), (165.37, 165.81);IR (CHCl₃) 3028, 2981, 2934, 1815, 1733, 1604, 1450, 1380, 1004 cm⁻¹.Anal. Calcd for C₁₂ H₂₃ NO₅ : C, 68.28; H, 6.28; N, 3.79. Found: C,68.07; H, 6.43; N, 3.72.

Example 41 (3R,4S)-1-tert-Butoxycarbonyl-4-cyclohexyl-3-(1-ethoxyethoxy)-2-azetidinone(Vb-g-EE)

91%; colorless oil; [α]_(D) ²⁰ +62.5° (c 1.12, CHCl₃); ¹ H NMR (250 MHz,CDCl₃) δ1.10-1.28 (m, 6H), 1.15 (t, J=7.0 Hz, 3H), [1.27 (d, J=5.4 Hz),1.31 (d, J=5.4 Hz), 3H], [1.45 (s), 1.46 (s), 9H], 1.63-1.70 (m, 5H),[3.43 (dq, J=9.2, 7.0 Hz), 3.62 (m), 3.75 (d, J=7.0 Hz), 3.78 (d, J=7.0Hz), 2H], 3.85 (t, J=6.1 Hz, 1H), [4.78 (q, J=5.4 Hz), 4.88 (m), 1H],[4.85 (d, J=6.1 Hz), 4.86 (d, J=6.1 Hz), 1H]; ¹³ C NMR (63 MHz, CDCl₃)δ15.07, (20.25, 20.37), (26.05, 26.14), 26.26, (27.33, 27.95), (29.05,29.20), (30.04, 30.23), (37.54, 37.64), (61.19, 62.53), (62.06, 62.32),(75.42, 75.85), 83.06, 100.11, 148.72, (166.70, 166.76); IR (neat) 2980,2931, 2854, 1807, 1725, 1450, 1370, 1329, 1212, 1118 cm⁻¹. Anal. Calcdfor C₁₈ H₃₁ NO₅ : C, 63.32; H, 9.15; N, 4.10. Found: C, 63.15; H, 8.97;N, 3.96.

Example 42(3R,4S)-1-tert-Butoxycarbonyl-3-(1-ethoxyethoxy)-4-(2-phenylethenyl)-2-azetidinone(Vb-h-EE)

86%; white solid; mp 69°-73° C.; ¹ H NMR (300 MHz, CDCl₃) δ [1.16 (t,J=7.1 Hz), 1.18 (t, J=7.1 Hz), 3H], [1.25 (d, J=5.4 Hz), 1.36 (d, J=5.4Hz), 3H], 1.48 (s, 9H), [3.47 (m), 3.62 (m), 3.80 (m), 2H], 4.68 (dd,J=5.8, 8.8 Hz, 1H), [4.82 (q, J=5.4 Hz), 4.91 (q, 5.4 Hz), 1H], [5.09(d, J=5.8 Hz), 5.11 (d, J=5.8 Hz), 1H], [6.23 (dd, J=8.8, 15.8 Hz), 6.25(dd, J=8.8, 15.8 Hz), 1H], [6.72 (d, J=15.8 Hz), 6.73 (d, J=15.8 Hz),1H], 7.27-7.44 (m, 5H); ¹³ C NMR (75 MHz, CDCl₃) δ14.98, 20.31, 27.98,60.24, 60.85, 61.46, 62.36, 63.58, 83.38, 99.63, 99.87, 122.45, 122.63,126.69, 128.20, 128.61, 136.15, 136.34, 136.38, 147.74, 147.79, 165.33,165.53; IR (KBr) 3027, 3020, 2984, 2933, 1809, 1723 cm⁻¹. Anal. Calcdfor C₂₀ H₂₇ NO₅ : C, 66.46; H, 7.53; N, 3.88 Found: C, 66.60; H, 7.50;N, 3.87.

Example 43(3R,4S)-1-tert-Butoxycarbonyl-3-(1-ethoxyethoxy)-4-(isobutyl)-2-azetidinone(Vb-i-EE)

80%; yellow oil; [α]_(D) ²⁰ +77.45° (c 0.216, CHCl₃); ¹ H NMR (300 MHz,CDCl₃) δ0.89 (d, J=5.7 Hz, 6H), 1.41 (t, J=7.1 Hz, 3H), [1.25 (d, J=5.3Hz ), 1.31 (d, J=5.3 Hz), 3H], 1.45 (s, 9H), 1.51-1.67 (m, 3H), [3.48(dq, J=9.3, 7.1 Hz), 3.55-3.71 (m, 1H), 3.80 (dq, J=9.3, 7.1 Hz), 2H],4.08 (q, J=6.1 Hz, 1H), [4.70 (q, J=5.3 Hz), 4.90 (q, J=5.3 Hz), 1H],4.85 (d, J=6.1 Hz, 1H); ¹³ C NMR (75 MHz, CDCl₃) δ14.95, (20.11, 20.28),(22.42, 22.59 ), 22.70, (24.89, 25.07), 27.83, (37.03, 37.31), (56.14,56.38), (61.07, 62.27), (75.65, 75.92), 82.98, 99.91, 148.1, (166.1,165.9); IR (neat) 2931, 2960, 2872, (1790, 1807), (1708, 1726), (1454,1465), 1332, 1256, 1048, 1158, 996, 955, 857, 834, 770 cm⁻¹. Anal. Calcdfor C₁₆ H₂₉ NO₅ : C, 60.93; H, 9.27; N, 4.44. Found: C, 61.19; H, 9.41;N, 4.37.

Example 44(3R,4S)-1-tert-Butoxycarbonyl-4-cyclohexylmethyl-3-(1-ethoxyethoxy)-2-azetidinone (Vb-j-EE)

93%; yellow oil; [α]_(D) ²⁰ +75.64° (c 0.78 CHCl₃); ¹ H NMR (300 MHz,CDCl₃) δ0.81-1.74 (m, 13H), 1.19 (t, J=7.1 Hz, 3H), 1.48 (s, 9H), [1.30(d, J=5.3 Hz), 1.35 (d, J=5.3 Hz), 3H], [3.45 (dq, J=9.3, 7.1 Hz),3.62-3.71 (m), 3.78 (dq, J=9.3, 7.1 Hz), 2H], 4.01 (m, 1H), [4.81 (q,J=5.3 Hz), 4.91 (q, J=5.3 Hz), 1H], [4.86 (d, J=6.1 Hz), 4.87 (d, J=6.1Hz), 1H]; ¹³ C NMR (75 MHz, CDCl₃) δ15.03, 20.19, 20.36, 26.10, 26.36,27.91, (33.17, 33.31), (33.35, 33.49), (34.33, 34.58), (35.39, 35.68),(55.77, 55.99), (61.14, 62.21), (75.74, 75.90), 82.96, (99.86, 99.95),147.96, 166.13; IR (neat) 2979, 2923, 2850, 1719, 1807, 1449, 1336, 1154cm⁻¹. Anal. Calcd. for C₁₉ H₃₃ NO₅ : C, 64.20; H, 9.36; N,3.94. Found:C, 64.00; H, 9.17; N, 4.02.

Examples 45-50 Preparations of1-(N-monosubstituted-carbamoyl)-3-(hydroxy-protected)-4-substituted-2-azetidinones(Vd)

To a solution of 0.5 mmol of a3-(1-hydroxy-protected)-4-substituted-2-azetidinone (VI) in 6 mL oftetrahydrofuran, was added dropwise at -78° C. 0.6 mmol of n-butylitheum(n-BuLi). After 5 min, 1 mmol of an isocyanate was added. The reactionmixture was stirred 30 min at -78° C. and quenched by addition of 2 mLsat. NH₄ Cl solution. The reaction mixture was diluted with 30 mL ofether and the organic layer was washed several times with brine, driedover Na₂ CO₃ and concentrated. The crude solid was purified bychromatography on silica gel to yield the corresponding N-carbamoylβ-lactam (Vd).

Example 45 (3R,4S)-3-(1-Ethoxyethoxy)-1-phenylcarbamoyl-4-phenyl-2-azetidinone(Vd-a-EE)

66%; pale yellow solid; mp 152°-155° C.; [α]_(D) ²⁰ +87.8° (C 0.9,CHCl₃); ¹ H NMR (250 MHz, CDCl₃) δ [1.07 (d, J=5.4 Hz), 1.13 (d, J=5.4Hz), 3H], 1.16 (t, J=7.1 Hz, 3H), [3.26 (dq, J=9.5, 7.1 Hz), 3.37 (q,J=7.1 Hz), 3.39 (q, J=7.1 Hz), 3.67 (dq, J=9.5, 7.1 Hz), 2H], [4.53 (q,J=5.4 Hz), 4.72 (q, J=5.4 Hz), 1H], 5.28 (m, 2H), [6.59 (bs), 6.60 (bs),1H], 7.10-7.55 (m, 10H), 8.68 (bs, 1H; ¹³ C NMR (63 MHz, CDCl₃) δ(15.04, 15.16), (19.98, 20.11), (60.99, 62.53), 61.80, (76.05, 76.66),(99.34, 99.70), (119.63, 120.69, 124.37, 127.67, 127.95, 128.40, 128.45,128.67, 128.85, 129.04, 129.12, 130.49), 133.48, (137.03, 137.28),(147.23, 147.29), (168.12, 168.52); IR (CHCl₃) 3342, 3017, 2982, 2932,1773, 1719, 1602, 1548, 1445, 1312, 1224, 1210 cm⁻¹. Anal. Calcd for C₂₀H₂₂ N₂ O₄ : C, 67.78; H, 6.26; N, 7.90. Found: C, 67.92; H, 5.98; N,8.17.

Example 46 (3R, 4S)-1-tert-Butoxycarbonyl-4-Phenyl-3-(1,1,1-trichloroethoxycarbonyl)-2-azetidinone (Vb-a-Troc)

White solid; mp 122°-124° C.; [α]_(D) ²⁰ +28° (c 0.5, CHCl₃); ¹ H NMR(250 MHz, CDCl₃) δ1.39 (s, 9H), 4.43 (d, J=11.7 Hz, 1H), 4.55 (d, J=11.7Hz, 1H), 5.28 (d, J=5.5 Hz, 1H), 5.76 (d, J=5.5 Hz, 1H), 7.30 (m, 5H);¹³ C NMR (63 MHz, CDCl₃) δ27.81, 60.80, 77.03, 78.76, 84.40, 127.73,128.58, 129.09, 131.55, 147.71, 152.17, 160.34; IR (CHCl₃) 3016, 2976,1819, 1771, 1732, 1683, 1244 cm⁻¹. Anal. Calcd for C₁₇ H₁₈ Cl₃ NO₆ : C,46.54; H, 4.14; N, 3.19. Found: C, 46.33; H, 4.34; N, 3.33.

Example 47 (3R,4S)-3-Acetyl-1-tert-butoxycarbonyl-4-phenyl-2-azetidinone(Vb-a-Ac)

White solid; mp 63°-64° C.; [α]_(D) ²⁰ +32.1° (c 0.81, CHCl₃); ¹ H NMR(250 MHz, CDCl₃) δ1.37 (s, 9H), 1.65 (s, 3H), 5.22 (d, J=5.5 Hz, 1H),5.83 (d, J=5.5 Hz, 1H), 7.23-7.33 (m, 5H); ³ C NMR (63 MHz, CDCl₃)δ19.71, 27.81, 60.84, 75.94, 84.07, 127.43, 128.31, 128.67, 132.44,147.25, 162.39, 168.83; IR (CHCl₃) 3026, 2984, 1815, 1752, 1731, 1497,1371, 1286, 1224, 1152, 1024 cm⁻¹. Anal. Calcd for C₆ H₁₉ NO₅ : C,62.94; H, 6.27; N, 4.59. Found: C, 63.17; H, 6.14; N, 4.52.

Example 48 (3R, 4S) -1-tert-Butylcarbamoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone (Vb-b-EE)

74%; pale yellow viscous oil; [α]_(D) ²⁰ +144.3° (C 0.7, CHCl₃); ¹ H NMR(250 MHz, CDCl₃) δ[0.96 (d, J=5.3 Hz), 1.05 (d, J=5.3 Hz), 3H], 1.10 (t,J=7.1 Hz, 3H), [1.33 (s), 1.34 (s), 9H], [3.21 (dq, J=9.3, 7.0 Hz), 3.30(q, J=7.0 Hz), 3.33 (q, J=7.1 Hz), 3.62 (dq, J=9.1, 7.0 Hz), 2H], [4.46(q, J=5.4 Hz), 4.66 (q, J=5.4 Hz) , 1H], 5.10-5.19 (m, 2H), [6.59 (bs),6.60 (bs), 1H], 7.23-7.36 (m, 5H); ¹³ C NMR (63 MHz, CDCl₃) δ (14.86,14.99), (19.75, 19.95), (28.81, 29.30), (60.62, 61.20), (60.80, 62.29),(75.57, 76.76), (98.91, 99.34), (127.07, 127.40, 127.70, 128.17, 128.29,128.53), (133.71, 133.86), (148.54, 148.59 ), (167.67, 168.13); IR(CHCl₃) 3362, 3035, 2977, 2932, 1767, 1710, 1605, 1537, 1457, 1366,1320, 1282, 1217, 1100 cm⁻¹. Anal. Calcd for C₁₈ H₂₆ N₂ O₄ : C, 64.65;H, 7.84; N, 8.38. Found: C, 64.46; H, 7.75; N, 8.39.

Example 49 (3R,4S)-1-Benzylcarbamoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone(Vb-c-EE)

50%; pale yellow viscous oil; [α]_(D) ²⁰ +66.2° (C .8, CHCl₃); ¹ H NMR(250 MHz, CDCl₃) δ[0.99 (d, J=5.5 Hz), 1.08 (d, J=5.5 Hz), 3H], 1.12 (m,3H), [3.16-3.40 (m), 3.63 (m), 2H], [4.35-4.55 (m), 4.69 (q, J=5.5 Hz),3H], 5.21 (m, 2H), [7.03 (bs), 7.05 (bs), 1H], 7.32 (m, 10H); ¹³ C NMR(63 MHz, CDCl₃) δ (15.01, 15.14), (19.90, 20.11), 43.83, (60.66, 62.44),(60.75, 61.54), (75.93, 77.04), (99.16, 99.56), (127.25, 127.64, 127.69,128.17, 127.93, 128.35, 128.55, 128.64, 128.74), (133.59, 133.76),137.80, 150.02, (167.73, 168.19); IR (CHCl₃) 3379, 3090, 3033, 2980,2930, 1773, 1707, 1604, 1536, 1455, 1319, 1270, 908 cm⁻¹. Anal. Calcdfor C₂₁ H₂₄ N₂ O₄ : C, 68.46; H, 6.57; N, 7.60. Found: C, 68.30; H,6.66; N, 7.51.

Example 50 (3R,4S)-3-(1-Ethoxyethoxy)-1-ethylcarbamoyl-4-phenyl-2-azetidinone (Vd-d-EE)

63%; pale yellow oil; [α]_(D) ²⁰ +96.7° (0.9, CHCl₃); ¹ H NMR (250 MHz,CDCl₃) δ[0.96 (d, J=5.3 Hz), 1.04 (d, J=5.3 Hz), 3H], 1.05-1.18 (m, 3H),[3.13-3.39 (m), 3.59 (m), 4H], [4.45 (q, J=5.3 Hz), 4.65 (q, J=5.3 Hz),1H], 5.16 (m, 2H), [6.60 (bs), 6.62 (bs), 1H], 7.27 (m, 5H); ¹³ C NMR(63 MHz, CDCl₃) δ14.98, (19.84, 29.93), 34.79, (60.56, 61.35), (60.72,62.35), (75.91, 77.03), (99.14, 99.54), (127.28, 127.55, 127.85, 128.27,128.40), (133.74, 133.89), (149.87, 149.93), (167.62, 168.07); IR(CHCl₃) 3378, 3035, 2980, 2934, 1774, 1704, 1537, 1455, 1321, 1271,1112, 1025 cm⁻¹.

Examples 51-52 Preparations of1-(N,N-disubstituted-carbamoyl)-3-(hydroxy-protected)-4-substituted-2-azetidinones(Vd)

A typical procedure is described for the preparation of(3R,4S)-(-)-1-morpholinecarbonyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone(Vc-b). To a solution of 30 mg (0.13 mmol) of3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone VIa-EE in 2 mL of CH₂ Cl₂, 2mg of DMAP and 0.05 mL of triethylamine was added at room temperature.After 5 min, 22.9 mg (0.15 mmol) of morpholinecarbonyl chloride wasadded. The reaction mixture was stirred for 2 h at room temperature. Thereaction mixture was diluted with 20 mL of CH₂ Cl₂ and the organic layerwas washed two times with brine, dried over Na₂ CO₃ and concentrated.The crude solid product was purified by chromatography on silica gel toyield pure Vc-b: 87%; pale yellow oil; ¹ H NMR (250 MHz, CDCl₃) δ[0.90(d, J=5.3 Hz), 1.01 (d, J=5.3 Hz)](3H), [1.04 (t, J=7.1 Hz), 1.18 (t,J=7.1 Hz)](3H), 3.20 (m, 4H), [3.28 (m), 3.53 (m), 3.67 (m)](2H), 3.60(m, 4H), [4.41 (q, J=5.3 Hz), 4.63 (q, J=5.3 Hz)](1H), {5.07 (d, J=5.8Hz), 5.08 (d, J=5.8 Hz)] (1H), [5.29 (d, J=5.8 Hz), 5.32 (d, J=5.8 Hz)](1H), 7.23-7.27 (m, 5H).

Example 52(3R,4S)-(-)-1-(N,N-Dimethylcarbomoyl)-3-(1-ethoxyethoxy)-4-phenyl-2-azetidinone(Vc-a)

55%; colorless liquid; ¹ H NMR (250 MHz, CDCl₃) δ[0.98 (d, J=5.4 Hz),1.10 (d, J=5.4 Hz)] (3H), 1.12 (t, J=7.1 Hz), 1.13 (t, J=7.1 Hz), 3H],3.16 (bs, 6H), [3.37 (m), 3.67 (m)] (2H), [4.47 (q, J=5.4 Hz), 4.71 (q,J=5.4 Hz)](1H), [5.11 (d, J=5.7 Hz), 5.12 (d, J=5.7 Hz)] (1H), 5.34 (t,J=5.7 Hz, 1H), 7.34 (m, 5H).

Examples 53-56 below provide methods of preparation of baccatins (III)and (IV) by using 14-OH-DAB, a natural compound, which was commerciallyobtained. Identification data for the baccatins (IIIa), (IIIb) (III-b)and (IVa) are shown following these examples.

Example 53 Preparation of7,10-diTroc-14-hydroxy-10-deacetylbaccatin-III-1,14-carbonate (IIIa)

14-Hydroxy-10-deacetylbaccatin III (14-OH-DAB) (910 mg, 1.63 mmol) wasdissolved in 18 mL of anhydrous pyridine. The solution was heated at 80°C. and 1 mL of trichloroethylchloroformate was added. After stirring for5 min, another 0.4 mL of trichloroethylchloroformate was added and themixture was stirred for 30 sec (total quantity oftrichloroethylchloroformate: 1.4 mL, 2.15 g, 9.71 mmol, approximately 6equivalents). The reaction flask was removed from the oil bath and thereaction mixture was checked by thin layer chromatography (TLC) toconfirm the completion of the reaction. Then, some drops of methanol anda piece of ice were added to remove the excess chloroformate. Thereaction mixture was extracted with CHCl₃ and the extract was washedwith 0.1N hydrochloric acid and saturated brine. After drying overanhydrous MgSO₄ and removal of the solvent, the residue was purified bycolumn chromatography on silica gel using EtOAc/hexanes (1:1) as theeluant to give 1.16 g (75%) of IIIa as a white solid. The identificationdata from IIIa is shown below: ¹ H NMR (CDCl₃) δ1.20 (s, 3H, H17), 1.28(s, 3H, H16), 1.88 (s, 3H, H19), 2.08 (m, 1H, H6β), 2.18 (s, 3H, H18),2.33, (s, 3H, 4-OAc), 2.63 (m, 1H, H6α), 3.75 (bs, 1H, H14), 3.82 (d,J=7.1 Hz, 1H, H3), 4.20 (d, J=8.4 Hz, 1H, H20β), 4.34 (d, J=8.4 Hz, 1H,H20α), 4.61 (d, J=11.8 Hz, 1H,Troc), 4.79 (s, 2H, Troc), 4.91 (d, J=11.8Hz, 1H, Troc), 4.97 (bs, 1H, H5), 5.01 (bs, 1H, OH), 5.01 (bs, 1H, H13),5.59, (dd, J=7.2, 10.6 Hz, 1H, H7), 6.10 (d, J=7.1 Hz, 1H, H2), 6.25 (s,1H, H10), 7.50 (m, 2H), 7.65 (m, 1H), 8.03 (d, 2H); ¹³ C NMR (CDCl₃)δ10.80, 15.22, 21.56, 22.21, 25.63, 33.05, 41.28, 46.71, 56.44, 68.93,71.79, 75.78, 76.00, 76.54, 77.56, 79.03, 79.91, 83.49, 84.09, 88.25,94.10, 127.87, 129.01, 129.86, 130.92, 134.38, 144.81, 152.76, 153.12,153.18, 164.73, 170.64, 199.97.

Example 54 Preparation of 14-Acetyl-7,10-DiTroc-14-hydroxy DAB (IIIb)

To a solution of 594 mg (0.654 mmol) of7,10-diTroc-14-hydroxy-10-deacetylbaccatin III (IIIa) in 30 mL ofpyridine, was added 230 mL (3.27 mmol, 5 equiv.) of acetyl chloride at-10° C. The reaction mixture was stirred at -10° C. for 24 h. Thereaction mixture was extracted with EtOAc and washed with 0.1Nhydrochloric acid and brine The extract was dried over anhydrous MgSO₄and concentrated in vacuo to give the crude product. The crude productwas purified by flash column chromatography on silica gel usingEtOAc/hexanes (1:1) as the eluant to give 402 mg (65%) of IIIb as awhite solid having the identification data listed below: mp 225°-226°C.; ¹ H NMR (CDCl₃) δ1.10 (s, 3H), 1.21 (s, 3H), 1.88 (s, 3H), 2.02 (s,3H), 2.05 (m, 1H, H6β), 2.19 (s, 3H), 2.38 (s, 3H), 2.64 (m, 1H, H6α),2.74 (s, 1H, OH), 3.19 (bs, 1H, OH), 3.98 (d, J=7.3 Hz, 1H, H3), 4.23(d, J=8.4 Hz, 1H, H20α), 4.30 (d, J=8.4 Hz, 1H, H20β), 4.61 (d, J=11.8Hz, 1H, TROC), 4.72 (m, 1H, H13), 4.77 (d, J=7.1 Hz, 1H, TROC), 4.91 (d,J=11.8 Hz, 1H, TROC), 4.98 (m, 1H, H5), 5.39 (d, J=5.4 Hz, 1H, H14),5.62 (dd, J=7.1, 10.5 Hz, 1H, H7), 5.84 (d, J=7.3 Hz, 1H, H2), 6.30 (s,1H, H10), 7.44-7.62 (m, 3H), 8.03-8.06 (m, 2H). Anal. Calcd for C₃₇ H₄₀Cl₆ O₁₆ : C, 46.61; H, 4.23. Found: C, 46.80; H, 4.39.

Example 55 Preparation of14-hydroxy-2-cyclohexanecarbonyl-2-debenzoyl-10-deacetyl baccatin III(III-B)

A suspension of 14-hydroxy10-deacetylbaccatin III (500 mg, 0.899 mmol)and 5% Rh-C catalyst (50 mg) in MeOH (8 mL) and EtOAc (2 mL) washydrogenated at 50° C. and 900 psi of hydrogen for 36 h. After thereaction mixture was cooled to room temperature, hydrogen gas wasreleased, the catalyst filtered off, and the solvents evaporated invacuo to give the crude product. The crude product was submitted topurification by column chromatography on silica gel using EtOAc/hexanes(1:1) as the eluant to give 498 mg (98%) of III-B as a white solidhaving the identification data listed below: ¹ H NMR (DMSO-d⁶) δ0.88 (s,6H), 1.46 (s, 3H), 1.86 (s, 3H), 2.14 (s, 3H), 1.12-2.24 (m, 13H), 3.59(m,2H), 3.93 (d, J=8.0 Hz, 1H), 3.99 (d, J=7.0 Hz, 1H), 4.25 (d, J=8.0Hz, 1H), 4.36 (m, 1H), 4.39 (s, 1H), 4.76 (d, J=2.0 Hz, 1H), 4.88 (bd,J=9.1 Hz, 1H), 4.96 (d, J=7.1 Hz, 1H), 5.08 (d, J=2.0 Hz, 1H), 5.29 (d,J=7.1 Hz, 1H), 5.45 (d, J=5.2 Hz, 1H), 6.64 (d, J=6.3 Hz, 1H); ¹³ C NMR(DMSO-d⁶) δ9.36, 14.51, 21.14, 22.05, 24.82, 25.04, 25.23, 26.40, 28.11,28.44, 36.41, 42.04, 42.56, 45.78, 57.17, 70.70, 72.21, 73.22, 74.08,74.54, 75.05, 75.39, 79.80, 83.58, 135.15, 139.11, 169.52, 174.62,209.87.

Example 56 Preparation of 7,10-DiTroc-14-hydroxy-10-deacetyl baccatinIII (IVa)

14-Hydroxy-10-deacetylbaccatin III (14-OH-DAB) (900 mg, 1.61 mmol) wasdissolved in 18 mL of anhydrous pyridine. The solution was heated at 80°C. and 0.92 mL (1.42 g, 6.44 mmol, 4 equivalents) oftrichloroethylchloroformate was added. After stirring for 5 min, thereaction flask was removed from the oil bath and the reaction mixturewas checked by thin layer chromatography (TLC) to confirm the completionof the reaction. Then, some drops of methanol and a piece of ice wereadded to remove the excess chloroformate. The reaction mixture wasextracted with CHCl₃ and the extract was washed with 0.1N hydrochloricacid and saturated brine. After drying over anhydrous MgSO₄ and removalof the solvent, the residue was purified by column chromatography onsilica gel using EtOAc/hexanes (1:1) as the eluant to give 808 mg (55%)of IVa as a white solid: ¹ H NMR (CDCl₃) δ1.10 (s, 3H, H17), 1.18 (s,3H, H16), 1.83 (s, 3H, H19), 2.02 (m, 1H, H6β), 2.14 (s, 3H, H18), 2.30(s, 3H, 4-OAc), 2.61 (m, 1H, H6α), 3.22 (m, 1H, OH), 3.61 (s, 1H, OH),3.66 (m, 1H, OH), 3.89 (d, J=7.1 Hz, H3), 4.01 (m, 1H, H14), 4.18 (d,J=8.4 Hz, 1H, H20β), 4.28 (d, J=8.4 Hz, 1H, H20α), 4.60 (d, J=11.9 Hz,1H, Troc), 4.73 (m, 1H, H13), 4.77 (s, 2H, Troc), 4.83 (d, J=11.9 Hz,1H, Troc), 4.95 (m, 1H, H5), 5.57 (dd, J=7.1, 10.6 Hz, 1H, H7), 5.79 (d,J=7.1 Hz, 1H, H2), 6.24 (s, 1H, H10), 7.40-7.60 (m, 3H), 8.02 (bd, 2H).

Examples 57-62 describe the syntheses of taxanes of the presentinvention by coupling of the β-lactams(V) with baccatins(III) and (IV)as prepared in previous examples. The coupling reactions took place inthe presence of a base as shown in Schemes 3 and 4. In Example 57 thehydroxyl groups at C7 and C10 were protected, however, deprotection wascarried out in Example 58. In Example 59 both coupling and deprotectiontook place for the syntheses of both taxanes Ib and Ic.

Examples 57-62 Synthesis of7,10-diTroc-10-deacetyl-14-hydroxy-Taxol-1,14-carbonate (Ia-diTroc)

To a solution of baccatin IIIa (86.9 mg, 0.093 mmol) andN-benzoyl-β-lactam Va-a-EE (47.3 mg, 0.14 mmol) in 3.0 mL of THF, wasadded sodium hexamethyl disilazide (NaHMDS) 0.13 mL (1.2 eq, 0.85M soln.in THF) at -40° C. over the period of 30 min. TLC analysis of thereaction mixture revealed that baccatin IIIa was completely consumed.The reaction mixture was quenched with 10 mL saturated NH₄ Cl solution.The reaction mixture was extracted with ether (10 mL×3), thendichloromethane (10 mL), and the combined extracts were washed withbrine, dried over anhydrous sodium sulfate and concentrated to give thecrude product. The crude product was purified by column chromatographyusing EtOAc/hexane (1/2) as the eluant to give 95.9 mg of2'-EE-7,10-diTroc-10-deacetyl-14-hydroxy-Taxol-1,14-carbonate as a whitesolid. This compound was treated with 0.5N hydrochloric acid in THF atroom temperature for 1 h. The reaction mixture was dried and purified bychromatography on silica gel using EtOAc/hexane (2/3) as the eluant togive 65.5 mg (75% overall yield) of taxane Ia-diTroc as a white solidhaving the identification data listed below: mp 178°-180° C.; [α]_(D) ²⁰-5.9° (c 0.85, CHCl₃); ¹ H NMR (CDCl₃) δ1.30 (S, 6H, H16,H17), 1.89 (s,3H, H19), 1.92, (s, 3H, H18), 2.08 (m, 1H, H6β), 2.56 (s, 3H, 4-OAc),2.62 (m, 1H, H6α), 3.81 (d, J=7.4 Hz, 1H, H3), 4.09 (bs, 1H, 2'-OH),4.24 (d, J=8.5 Hz, 1H, H20β), 4.31, (d, J=8.5 Hz, 1H, H20α), 4.60 (d,J=11.9 Hz, 1H, Troc), 4.76 (s, 2H, Troc), 4.87-4.94 (m, 4H, Troc,H5,H2', H14), 5.55 (dd, J=7.1, 10.5 Hz, 1H, H7), 5.93 (dd, J=2.8, 8.9 Hz,1H, H3'), 6.11 (d, J=7.4 Hz, 1H, H2), 6.19 (s, 1H, H10), 6.47 (d, J=6.2Hz, 1H, H13), 7.21 (d, J=8.9 Hz, 1H, NH), 7.31-7.64 (m, 11H), 7.75 (d,J=7.4 Hz, 2H), 8.12 (d, J=7.4 Hz, 2H); ¹³ C NMR (CDCl₃) δ10.93, 14.63,22.39, 22.51, 25.39, 33.07, 41.64, 46.39, 54.92, 56.47, 68.88, 73.87,74.42, 75.78, 75.88, 77.22, 77.45, 78.29, 79.61, 80.17, 83.59, 88.01,94.02, 94.07, 126.80, 127.31, 127.73, 128.34, 128.64, 129.07 (2),130.16, 132.04, 132.46, 133.44, 134.35, 137.53, 139.71, 151.63, 153.06153.15, 164,79, 167.69, 171.37, 172.03, 199.33; IR (CHCl₃) 3038, 2951,1820, 1761, 1737, 1667, 1479, 1379, 1250, 1220; Anal. Calcd for C₅₂ H₄₉NCl₆ O₁₉ : C, 51.85; H, 4.10; N, 1.16. Found: C, 51.67; H, 3.86; N,1.13.

Example 58 Synthesis of 10-deacetyl-14-hydroxy-Taxol-1,14-carbonate (Ia)

Taxane Ia-diTroc (100 mg) was treated with Zn dust (200 mg) in aceticacid at 40° C. for several hours. The reaction mixture was filtered on aglass filter and the filtrate was condensed in vacuo. The residue wasredissolved in CH₂ Cl₂, and Zn salt was removed by filtration to givethe crude product. The crude product was recrystalized usingEtOAc/hexane (3:1) to give pure taxane Ia (48 mg, 72 %) as a whitepowder: ¹ H NMR (CDCl₃) δ1.21 (s, 3H), 1.27 (s, 3H), 1.78 (s, 3H), 1.85(m, 1H, H6β), 2.04 (s, 3H), 2.54 (s, 3H, 4-OAc), 2.56 (m, 1H, H6α), 3.80(d, J=7.6 Hz, 1H, H3), 3.93 (d, J=4.4 Hz, 1H, 2'-OH), 4.28 (m, 4H, H20,H7, OH), 4.88 (m, 3H, H5, H14, H2'), 5.16 (s, 1H, H10), 5.93 (m, 1H,H3'), 6.07 (d, J=7.6 Hz, 1H, H2), 6.44 (d, J=5.8 Hz, 1H, H13), 7.23-7.60(m, 12H), 7.73 (bd, 2H), 8.14 (bd, 2H); ¹³ C NMR (CDCl₃) δ10.10, 14.22,14.39, 21.11, 22.17, 22.61, 25.57, 36.67, 41.62, 45.97, 54.71, 57.86,60.47, 69.43, 71.63, 73.82, 73.99, 74.66, 76.18, 77.27, 79.76, 80.43,84.13, 88.37, 126.79, 127.40, 127.91, 128.28, 128.59, 129.07, 130.22,131.98, 133.56, 134.25, 135.76, 136.22, 137.67, 151.89, 165.02, 167.67,171.09, 172.06, 209.76.

Example 59 Synthesis of 13-[(2R,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-3-phenylpropanoyl]-10-deacetyl-14-hydroxybaccatin-III-1,14-carbonate(Ib)

To a solution of baccatin IIIa (100 mg, 0.107 mmol) and N-t-BOC-β-lactamVb-d-EE (52 mg, 0.155 mmol) in 3.0 mL of THF, was added NaHMDS 0.12 mL(1.1 eq, 1.0M soln. in THF) at -30° C. over the period of 10 min. TLCanalysis of the reaction mixture revealed that baccatin IIIa wascompletely consumed. The reaction mixture was poured into a 100 mLbeaker which contained 10 mL saturated NH₄ Cl solution to quench thereaction. The reaction mixture was extracted with ether (10 mL×3), thendichloromethane (10 mL), and the combined extracts were washed withbrine, dried over anhydrous sodium sulfate and concentrated to give alight yellow solid (170 mg). The crude product was purified by columnchromatography on silica gel using EtOAc/hexane (1/1) as the eluant toafford taxane13-[(2R,3S)-3-(tert-butoxycarbonyl)amino-2-EEO-3-phenylpropanoyl]-10-deacetyl-14-hydroxybaccatin-III-1,14-carbonate(Ic-EE) (118 mg, 88%) as a white solid. The product was directly usedfor the next step to remove EE and Troc protecting groups all at once.

The crude taxane Ic-EE (157 mg) was treated with Zn dust (480 mg) in 2mL glacial acid at room temperature for 8 hrs, then the temperature wasraised to 50° C. for 4 hours. The solution was filtered, and thefiltrate was poured into ice-cold saturated sodium bicarbonate solution(20 mL). The solution was extracted with dichloromethane (20 mL), theextract was dried over anhydrous MgSO₄, and concentrated to give a whitesolid, which was further purified by column chromatography on silica gelusing EtOAc/hexane (2/1) as the eluant to afford taxane Ic (63 mg, 70%overall yield from the baccatin IIIa) having the identification datashown below: mp 190° C. (decomp.); [α]_(D) ²⁰ -22.83° (c, 0.193, CHCl₃);¹ H NMR (300 MHz, CDCl₃) δ1.36 (s, 9H, t-Boc), 1,77 (s, 3H, H₁₉), 1.82(m, 1H, H_(6b)), 1.87 (S, 3H, H₁₈), 2.43 (bs, 3H, 4-OAc), 2.55 (m, 1H,H_(6a)), 3.69 (bs, 1H, OH), 3.80 (d, J=7.5 Hz, H3), 4.20˜4.30 (m, 3H,H₂₀, H₅), 4.69 (s, 1H, OH), 4.75 (d, J=6.7 Hz, H₁₄), 4.92 (d, J=8.5 Hz,1H, H₇), 5.19 (s, 1H, H₁₀), 5.30 (m, 1H, H_(3')), 5.62 (d, J=8.6 Hz, 1H,H_(2')), 6.01 (d, J=7.5 Hz, 1H, H₂), 6.45 (d, J=5.9 Hz, 1H, H₁₃),7.51-7.64 (m, 8H), 8.02 (d, J=7.3 Hz); ¹³ C NMR (75 MHz, CDCl₃) δ9.97,14.37, 21.98, 22.52, 25.69, 28.24, 29.68, 36.74, 41.67, 45.94, 57.91,69.36, 71.65, 74.09, 74.31, 74.82, 76.09, 79.64, 80.58, 83.98, 88.09,126.61, 128.13, 128.96, 129.93, 134.18, 135.82, 136.52, 138.00,151.87,155.70, 164.78, 170.64, 171.89, 209.69; IR (neat) 3403, 2931,1817(amide), 1734, 1715, 1703, 1242, 1085. Anal. Calcd for C₄ H₅₁ NO₁₆ :C, 62.18; H, 6.05; N, 1.65. Found: C, 61.91; H, 6.33; N, 1.61.

Example 60 Synthesis of 14-[(2R, 3S)-3-(N-Benzoyl)amino-2-hydroxy-3-phenylpropanoyl]-10-deacetyl-14-hydroxybaccatin III(IIa)

To a solution of baccatin IVa (79.6 mg, 0.09 mmol) andN-benzoyl-β-lactam Va-a-EE (45.8 mg, 0.14 mmol) in 3.0 mL of THF, wasadded NaHMDS 0.13 mL (1.2 eq, 0.85M soln. in THF) at -40° C. over theperiod of 30 min. TLC analysis of the reaction mixture revealed thatbaccatin IIIa was completely consumed. The reaction mixture was quenchedwith 10 mL saturated NH₄ Cl solution. The reaction mixture was extractedwith ether (10 mL×3), then dichloromethane (10 mL), and the combinedextracts were washed with brine, dried over anhydrous sodium sulfate andconcentrated to give the crude product. The crude product was purifiedby column chromatography on silica gel using EtOAc/hexanes (1:3) as theeluant to give 90.2 mg (82 %) of 14-[(2R,3S)-3-(N-Benzoyl)amino-2-EEO-3-phenylpropanoyl]-10-deacetyl-14-hydroxy-baccatinIII (IIa-EE) as a white solid. This protected taxane IIa-EE was treatedwith Zn in acetic acid at 60° C. for 9 h. The reaction mixture wasfiltered on a glass filter and the filtrate was condensed in vacuo. Theresidue was redissolved in CH₂ Cl₂, and Zn salt was removed byfiltration to give the crude product. This crude product was purified bycolumn chromatography on silica gel using EtOAc/hexanes (3:1) as theeluant to give 33.7 mg (75 %) of taxane IIa as a white powder having theidentification data shown below: mp 198°-202° C.; [α]_(D) ²⁰ -13.2 (c0.38, MeOH) ;¹ H NMR (CDCl₃) δ1.17 (s, 3H), 1.20 (s, 3H), 1.74 (s, 3H,H19), 1.84 (m, 1H, H6b), 2.14 (s, 3H, H18), 2.17 (s, 3H, 4-OAc), 2.60,(m, 1H, H6a), 3/07 (bs, 1H, 2'-OH), 4.03 (d, J=6.6 Hz, 1H, H3), 4.14 (d,J=8.4 Hz, 1H, H20), 4.27 (m, 3H, H20, H7, 10-OH), 4.55 (m, 1H, H2'),4.99 (bd, 1H, H5), 5.07 (m, 1H, H13), 5.17 (d, J=5.8 Hz, 1H), 5.34 (s,1H, H10), 5.65 (d, J=5.7 Hz, 1H, H14), 5.83 (bd, 2H, H2, H3'), 6.91 (d,J=9.4 Hz, 1H, NH), 7.36-7.59 (m, 11H), 7.77 (bd, 2H), 8.15 (bd, 2H); ¹³C NMR (CDCl₃) δ9.53, 15.32, 20.66, 22.08, 26.03, 29.69, 37.06, 42.85,46.50, 54.68, 58.00, 71.63, 72.06, 73.60, 75.03, 76.60, 77.12, 78.82,80.31, 83.98, 127.10, 127.24, 128.25, 128.42, 128.84, 129.04, 130.62,132.51, 133.59, 135.04, 137.89, 140.68, 166.49, 168.13, 170.86, 172.12,211.58; IR (CHCl₃) n 3632, 3434, 3026, 3016, 2943, 2838, 1724, 1648;Anal. Calcd for C₄₅ H₄₉ NO₁₄ : C, 65.29; H, 5.97; N, 1.69. Found: C,65.15; H, 6.01; N, 1.79.

This example included a deprotection step to obtain taxane (IIa) asshown in Scheme 4.

Example 61 Synthesis of 7,10-diTroc-14-[(2R,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-3-phenylpropanoyl]-10-deacetyl-14-hydroxybaccatinIII (IIb-diTroc)

To a solution of 50 mg (0.055 mmol) of baccatin IVa in 10 mL of THF,0.06 mL (0.06 mmol) of NaHMDS was added at -40° C. over 10 min period. Asolution of 25 mg (0.083 mmol) of N-t-BOC-β-lactam Vb-d-EE in THF wasadded at -40° C. and stirred for 1 hr. The reaction was quenched byaddition of saturated NH₄ Cl at -40° C. The organic layer was separatedand the aqueous layer was extracted with ethyl acetate. The combinedorganic extracts were dried over anhydrous Na₂ CO₃ and concentrated invacuo. The crude product was purified by column chromatography on silicagel using EtOAc/hexanes (1:3) as the eluant to give 54.2 mg (82 %) of7,10-diTroc-14-[(2R,3S)-3-(tert-butoxycarbonyl)amino-2-EEO-3-phenylpropanoyl]-10-deacetyl-14-hydroxybaccatinIII (IIb-diTroc-EE) as a white solid. This protected taxaneIIb-diTroc-EE was treated with 0.5N HCl in THF at room temperature for 1hr. The reaction mixture was dried over nhydrous Na₂ CO₃ and purified bycolumn chromatography on silica gel using ETOAc/hexanes (1:3) as theeluant to give 40.0 mg (81%) of taxane IIb-diTroc as a white powder: ¹ HNMR (CDCl₃) δ1.19 (s, 3H, H17), 1.24 (s, 3H, H16), 1.45 (s, 9H), 1.85(s, 3H), 2.03 (m, 1H, H6b), 2.24 (s, 3H, H18), 2.37 (s, H, 4-OAc), 2.65(m, 1H, H6a), 3/01 (d, J=5.7 Hz, 1H, OH), 4.01 (d, J=6.8 Hz, 1H, H3),4.15 (d, J=8.4 Hz, 1H, H20), 4.32 (d, J=8.4 Hz, 1H, H20), 4.36 (d, J=5.6Hz, 1H, NH), 4.62 (d, J=11.8 Hz, 1H), 4.79 (s, 2H), 4.92 (d, J= 11.8 Hz,1H), 4.95-5.02 (m, 3H, H2', H5, OH), 5.18 (d, J=9.5 Hz, 1H, H13), 5.34(d, J=9.5 Hz, H, H14), 5.63 (dd, J=7.2, 10.5 Hz, 1H, H7), 5.71 (d, J=5.1 Hz, 1H, H3'), 5.84 (d, J=6.8 Hz, 1H, H2), 6.34 (s, 1H, H10),7.29-7.60 (m, 8H), 8.12 (bd, 2H); ¹³ C NMR (CDCl₃) δ15.33, 22.25, 28.11,28.17, 28.30, 28.45, 28.50, 33.26, 42.85, 46.82, 55.98, 56.51, 71.88,73.05, 73.60, 76.22, 76.57, 77.61, 77.67, 77.88, 79.65, 80.01, 81.31,83.54, 83.60, 94.21, 126.97, 128.29, 128.37, 128.74, 128.92 130.48,131.21, 133.67, 138.55, 144.71, 153.07, 153.22 156.23, 166.22, 171.04,171.97, 200.88;

This example shows only the coupling of baccatin(IVa) withβ-lactams(Vb-d) protected with EE to obtain a protected taxane as shwonin Scheme 4. In this example the taxane which was obtained wasIIb-diTroc.

Example 62 Synthesis of 14-[(2R,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-3-Phenylpropanoyl]-10-deacetyl-14-hydroxybaccatin III(IIb)

To a solution of 108 mg (0.09 mmol) of IIb-diTroc in 2 mL of acetic acidand 3 mL of MeOH, 240 mg of Zn (activated) was added at roomtemperature. The temperature was increased to 60° C. and the mixture wasstirred for 2 hrs. The reaction mixture was filtered on a glass filterand the filtrate was condensed in vacuo. The residue was redissolved inCH₂ Cl₂, and Zn salt was removed by filtration to give 116 mg of crudeproduct. This crude product was purified by column chromatography onsilica gel using EtOAc/hexanes (4:1) as the eluant to give 48.8 mg (70%) of taxane IIb as a white powder: ¹ H NMR (CDCl₃) δ1.15 (s, 3H), 1.16(s, 3H), 1.45 (s, 9H), 1.73 (s, 3H), 1.81 (m, 1H, H6b), 2.13 (s, 3H),2.36 (s, 3H), 2.60 (m, 1H, H6a), 3/03 (d, J=5.7 Hz, 1H, OH), 4.02 (d,J=6.9 Hz, 1H, H3), 4.17 (d, J=8.5 Hz, 1H, H20), 4.25-4.34 (m, 4H, H20,H7), 4.83 (d, J=6.0 Hz, 1H), 4.99 (m, 2H, H2', H 5), 5.18 (d, J=9.5 Hz,1H, H13), 5.31 (s, 1H, H10), 5.37 (d, J=9.5 Hz, 1H, H14), 5.67 (d, J=6.0Hz, 1H, H3'), 5.83 (d, J=6.9 Hz, 1H, H2), 7.31-7.56 (m, 8H), 8.12 (bd,2H);

This example illustrates the deprotection step of IIb-diTroc to obtainthe taxane IIb as shown in Scheme 4.

The procedures set forth above describe highly sophisticated and elegantprotocols for production of significantly enhanced compounds useful inthe treatment of cancer.

Thus, while there have been described what are presently believed to bethe preferred embodiments of the present invention, those skilled in theart will realize that other and further modifications can be made to theinvention without departing from the true spirit of the invention, suchfurther and other modifications are intended to be included hereinwithin the scope of the appended claims.

We claim:
 1. A compound of the formula (I) ##STR15## wherein R¹ is anunsubstituted or substituted straight chain or branched alkyl, alkenylor alkynyl radical, an unsubstituted or substituted aryl or heteroarylradical, an unsubstituted or substituted cycloalkyl, heterocycloalkyl,cycloalkenyl or heterocycloalkenyl radical;R² is an unsubstituted orsubstituted straight chain or branched alkyl, alkenyl or alkynyl,cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl orheteroaryl radical; or R² is an RO--, RS-- or RR'N-- wherein R is anunsubstituted or substituted straight chain or branched alkyl, alkenylor alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl or heteroaryl radical; R' is a hydrogen or R asdefined above; R and R' can be connected to form a cyclic structure; R³is a hydrogen or an acyl or an alkyl or an alkenyl or an alkynyl or anunsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenylor heterocycloalkenyl radical, or an unsubstituted or substituted arylor heteroaryl radical or a hydroxyl protecting group; R⁴ is a hydrogenor an acyl radical or an alkyl, alkenyl or alkynyl radical, anunsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenylor heterocycloalkenyl radical, an unsubstituted or substituted aryl orheteroaryl radical, or a hydroxyl protecting group; R⁵ is a hydrogen oran acyl radical or an alkyl, alkenyl or alkynyl radical, anunsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenylor heterocycloalkenyl radical, an unsubstituted or substituted aryl orheteroaryl radical, or a hydroxyl protecting group; R⁶ is a hydrogen oran acyl radical or an alkyl, alkenyl or alkynyl radical, anunsubstituted or substituted cycloalkyl, heterocycloalkyl, cycloalkenylor heterocycloalkenyl radical, an unsubstituted or substituted aryl orheteroaryl radical, or a hydroxyl protecting group; R⁵ and R⁶ can beconnected to form a cyclic structure; R⁷ is an acyl group; R⁸ is anhydrogen or a hydroxyl protecting group;wherein, whenever R¹ is a phenylradical, said phenyl radical is substituted with at least one halogen,hydroxyl, amino, mercapto, cyano, carboxyl group; alkoxy, alkylamino,dialkylamino, alkylthio, alkoxycarboxyl group wherein said alkyl portionhas 1 to 15 carbon atoms; aryloxy, arylthio, aryloxycarbonyl, whereinsaid aryl portion has 6 to 20 carbon atoms; or heteroarylthio,heteroaryloxy carbonyl wherein said heteroaryl portion has 3 to 15carbon atoms.
 2. A compound of the formula (I) ##STR16## wherein R¹ isan unsubstituted or substituted straight chain or branched alkyl,alkenyl or alkynyl radical, an unsubstituted or substituted aryl orheteroaryl radical, an unsubstituted or substituted cycloalkyl,heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical;R² is anunsubstituted or substituted straight chain or branched alkyl, alkenylor alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, aryl or heteroaryl radical; or R² is an RO--, RS--or RR'N-- wherein R is an unsubstituted or substituted straight chain orbranched alkyl, alkenyl or alkynyl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl radical; R' is ahydrogen or R as defined above; R and R' can be connected to form acyclic structure; R³ is a hydrogen or an acyl or an alkyl or an alkenylor an alkynyl or an unsubstituted or substituted cycloalkyl,heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, or anunsubstituted or substituted aryl or heteroaryl radical or a hydroxylprotecting group; R⁴ is a hydrogen or an acyl radical or an alkyl,alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl,heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, anunsubstituted or substituted aryl or heteroaryl radical, or a hydroxylprotecting group; R⁵ is a hydrogen or an acyl radical or an alkyl,alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl,heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, anunsubstituted or substituted aryl or heteroaryl radical, or a hydroxylprotecting group; R⁶ is a hydrogen or an acyl radical or an alkyl,alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl,heterocycloalkyl, cycloalkenyl or heterocycloalkenyl radical, anunsubstituted or substituted aryl or heteroaryl radical, or a hydroxylprotecting group; R⁵ and R⁶ can be connected to form a cyclic structure;R⁷ is an acyl group; R⁸ is an hydrogen or a hydroxyl protectinggroup;wherein R¹ is a radical selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl,isoctyl, cyclohexylmethyl, cyclohexylethyl, benzyl, phenylethyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and adamantyl, vinyl, allyl, 2-phenylethenyl,2-furylethenyl, 2-pyrrolyl-ethenyl, 2-pyridylethenyl, 2-thienylethyl,ethynyl, propargyl, tolyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,4-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, naphthyl,furyl, pyrrolyl, pyridyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,oxiranyl, pyrrolidinyl, piperidinyl, tetrahydrofuryl, tetrahydropyranyl,dihydrofuryl, dihydropyrrolyl, dihydropiranyl, and dihydropyridyl. 3.The compound according to the claim 1 whereinR¹, R² and R areindependently a straight chain or branched alkyl radical having 1 to 10carbon atoms, a straight chain or branched alkenyl radical having 2 to10 carbon atoms, or a straight chain or branched alkynyl radical having2 to 10 carbon atoms, a cycloalkyl radical having 3 to 10 carbon atoms,a heterocycloalkyl radical having 3 to 10 carbon atoms, a cycloalkenylradical having 3 to 10 carbon atoms, a heterocycloalkenyl radical having3 to 10 carbon atoms, a polycycloalkyl radical having 6 to 20 carbonatoms, an aryl radical having 6 to 20 carbons, a heteroaryl radicalhaving 3 to 15 carbon atoms; or R² is RO--, RS-- or RR'N-- radicalwherein R is as defined above, R' is a hydrogen or R as defined above; Rand R' can be connected to form a cyclic structure which has 2 to 10carbon atoms; R³, R⁴, R⁵ or R⁶ are each hydrogen or an acyl radicalhaving 1 to 20 carbons or R as defined above or a hydroxyl protectinggroup; R⁷ is an acyl group having 1 to 20 carbons; R⁸ is a hydrogen or ahydroxyl protecting group.
 4. The compound according to claim 1whereinR¹ is a tolyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,4-fluorophenyl, 4-trifluoromethylphenyl, 4-hydroxyphenyl,1-naphthyl,2-naphthyl, pyridyl, furyl, thienyl, pyrrolyl, N-methylpyrrolyl,2-phenylethenyl, 2-furylethenyl, 2-pyridylethenyl, 2thienylethenyl,2-phenylethyl, 2-cyclohexylethyl, cyclohexylmethyl, isobutyl orcyclohexyl; R² is selected from the group consisting of phenyl, tolyl,4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, biphenyl, 1-naphthyl,2-naphthyl, isopropyl, isobutyl, neopentyl, hexyl, heptyl, cyclohexyl,cyclohexylmethyl, benzyl, phenylethyl, and phenylethenyl; or R² is RO--wherein R is selected from the group consisting of a methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, isohexyl, cyclohexyl, phenyl, benzyl and9-fluorenylmethyl; or R² is RR'N-- selected from the group consisting ofa methylamino, ethylamino, propylamino, isopropylamino, butylamino,isobutylamino, tert-butylamino, neopentylamino, cyclohexylamino,phenylamino or benzylamino, dimethylamino, diethylamino, dipropylamino,dibutylamino, dipentylamino, dihexylamino, dicyclohexylamino,methyl(tert-butyl)amino, cyclohexyl(methyl)amino, methyl(phenyl)amino,pyrrolidiono, piperidino, or morpholino group; R³ and R⁴ are selectedfrom the group consisting of a hydrogen, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, and trifluoroacetyl, benzoyl,phenylacetyl, acryloyl, and crotyl, cinnamoyl, allyl, benzyl,methoxymethyl, methoxyethyl, 1-ethoxyethyl, tetrahydropyranyl,2,2,2-trichloroethoxylcarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl,9-fluroenylmethoxycarbonyl, trimethylsilyl, triethylsilyl,(tert-butyl)dimethylsilyl; R⁵ is selected from the group consisting of ahydrogen, acetyl, chloroacetyl, allyl, benzyl, acryloyl, crotyl, andcinnamoyl and R⁶ is a hydrogen; wherein R⁵ and R⁶ are connected to forma cyclic structure selected from the group consisting of carbonyl,propylidene, butylidene, pentylidene, phenylmethylidene,dimethylmethylidene, diethylmethylidene, dipropylmethylidene,dibutylmethylidene, methoxymethylidene, ethoxymethylidene, methylene,ethylene, and propylene; R⁷ is selected from the group consisting ofbenzoyl and cyclohexanecarbonyl; R⁸ is selected from the groupconsisting of a hydrogen, 1-ethoxyethyl, 2,2,2-trichloroethoxylcarbonyl,trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl.
 5. Thecompound according to claim 4 whereinR¹ is a phenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-fluoromethyl, 4-trifluoromethylphenyl, furyl,2-phenylethenyl, 2-phenylethyl, 2-cyclohexylethyl, 2-furylethenyl,2-phenylethyl, 2-cyclohexylethyl, cyclohexylmethyl or cyclohexyl; R² isselected from the group consisting of phenyl, tolyl, 4-methoxyphenyl,biphenyl, 1-naphthyl, 2-naphthyl, isobutyl, pentyl, neopentyl, hexyl,cyclohexyl, cyclohexylmethyl, benzyl, phenylethyl, and phenylethenyl; orR² is RO-- wherein R is selected from the group consisting of a methyl,ethyl, butyl, tert-butyl, cyclohexyl, phenyl, and benzyl; or R² isRR'N-- selected from the group consisting of an ethylamino,tert-butylamino, phenylamino, benzylamino, dimethylamino and morpholinogroup; R³ is a hydrogen, triethylsilyl or2,2,2-trichloroethoxylcarbonyl; R⁴ is a hydrogen, acetyl or2,2,2-trichloroethoxylcarbonyl; R⁵ is an acetyl; R⁶ is a hydrogen; andR⁵ and R⁶ are connected to form a carbonate; R⁷ is benzoyl orcyclohexanecarbonyl; R⁸ is a hydrogen, 1-ethoxyethyl, triethylsilyl, ortert-butyldimethylsilyl.
 6. The compound according to claim 4 whereinR¹is a alkyl; R² is phenyl or tert-butoxy; R³ is a hydrogen, triethylsilylor 2,2,2-trichloroethoxylcarbonyl; R⁴ is a hydrogen, acetyl or2,2,2-trichloroethoxylcarbonyl; R⁵ is an acetyl and R⁶ is a hydrogen; orR⁵ and R⁶ are connected to form a carbonate; R⁷ is benzoyl; R⁸ is ahydrogen or 1-ethoxyethyl.
 7. A pharmaceutical composition havingantineoplastic activity comprising the compound of claim 1 and aphysiologically acceptable carrier therefor.
 8. A method for treatingtumors selected from the group consisting of ovarian, breast, non-smallcell lung and colon cancer which comprises administering to a patient aneffective antitumor amount of the compound of claim 1.